Method of treating disease

ABSTRACT

The present disclosure relates to methods for treating a variety of diseases and/or ameliorating pain by administering to the ear canal of a subject a composition.

This application is a continuation of U.S. patent application Ser. No. 15/978,742, which is a continuation-in-part of U.S. patent application Ser. No. 14/931,581, which is a continuation-in-part of International Application No. PCT/US2014/036855, filed May 5, 2014, which claims priority to U.S. Provisional Application Ser. No. 61/819,023, filed May 3, 2013; and this application is also a continuation-in-part of U.S. patent application Ser. No. 14/270,238, filed on May 5, 2014, which claims benefit and priority to U.S. Provisional Application Ser. 61/819,023, filed on May 3, 2013, the contents of each of which are hereby incorporated by reference in their entireties. The specification, figures and complete disclosure of U.S. Provisional Application No. 61/819,023, PCT/US2014/036855, U.S. patent application Ser. No. 14/270,238 and U.S. patent application Ser. No. 14/931,581 and U.S. patent application Ser. No. 15/978,742 are incorporated herein by specific reference for all purposes.

All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.

FIELD OF THE INVENTION

The present disclosure relates to methods for treating a variety of diseases and/or ameliorating pain by administering to the ear canal of a subject a composition.

BACKGROUND OF THE INVENTION

Sympathetic presynaptic nerve cell bodies are located in the lateral horn of spinal cord segments T1-L2. Sympathetic postsynaptic cell bodies are in ganglia, either sympathetic chain ganglia or prevertebral ganglia. Sympathetic presynaptic fibers get to the sympathetic chain via white rami communicantes and either synapse at the level they enter, ascend or descend to synapse, or leave the sympathetic trunk without synapsing as a splanchnic nerve to go to a prevertebral ganglion. Sympathetic postsynaptic fibers may enter the spinal nerves via gray rami communicantes to be distributed with dorsal and ventral primary rami, may form perivascular plexuses to be distributed with blood vessels, or may travel to the target organ directly. The sympathetic nervous system provides sympathetic innervation to essentially every part of the body.

Parasympathetic presynaptic cell bodies are located in the brainstem and the lateral horns of spinal cord segments S2, S3, and S4 and leave the CNS in cranial nerves III, VII, IX and X, and in pelvic splanchnic nerves arising from the ventral primary rami of spinal nerves S2, S3, and S4. The parasympathetic postsynaptic cell bodies are located in four pairs of ganglia in the head (associated with cranial nerves III, VII and IX), and otherwise in microscopic ganglia either on or in the wall of the target organ. The distribution of the parasympathetic nervous system is more limited than the sympathetic nervous system, with cranial nerves III, VII and IX supplying smooth muscle and glands of the head, the vagus nerve supplying the visceral organs up to the left colic flexure, and the pelvic splanchnics supplying the descending and sigmoid colon, rectum and pelvic viscera. With the exception of the external genitalia, the parasympathetic nervous system does not reach the body wall.

The autonomic nervous system allows vertebrate species to go about their daily business without having to think about the mechanics of their organs. Hearts beat, intestines digest, blood vessels change diameter, and vertebrates adapt appropriately to any situation, all without our having to think about it.

SUMMARY OF THE INVENTION

The invention provides for methods for treating a variety of diseases that comprises performing topical auricular anesthesia of the external auditory canal for the purposes of anesthetizing cranial nerves 5, 7, 9, 10, 11, and 12, along with the parasympathetic nervous system, the sympathetic nervous system. In one embodiment, the invention provides for auricular anesthesia of the autonomic nervous system. In one embodiment, auricular anesthesia is performed on the trigeminal nerve, facial nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, hypoglossal nerves, or a combination thereof. The invention further provides for modulation of the general somatic nervous system and the general visceral nervous system by administering an otic pharmaceutical composition comprising one or more anesthetics (such as lidocaine and/or tetracaine) in solution with a pharmaceutical carrier (such as an excipient) glycerine, and with or without epinephrine. In some embodiments, the otic pharmaceutical composition further comprises an analgesic, such as a pyrazolone derivative. In some embodiments, the pyrazolone derivative is antipyrene. The invention provides methods for treating a variety of diseases that comprises performing auricular anesthesia of the sympathetic nervous system via the vagus nerve to the sympathetic plexus. The invention also provides methods for treating pain from any variety of diseases disclosed herein by performing auricular anesthesia of the vagus nerve directly and the sympathetic nerve indirectly thus blocking general somatic afferent signals and general visceral afferent signals. The invention further provides methods of blocking pain from a variety of diseases that comprises performing auricular anesthesia of the vagus nerve with resultant anesthesia to the thalamic nuclei resulting in modulation of general visceral afferent pain and general somatic afferent pain. In various embodiments, the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction.

In various embodiments, the present invention provides a safe and non-invasive procedure, by which to treat a host of human diseases, and their symptoms, that are associated with the fifth cranial nerve (trigeminal nerve), the seventh cranial nerve (facial nerve), ninth cranial nerve (glossopharyngeal nerve), and the tenth cranial nerve (vagus nerve). The present disclosure provides a method of disrupting the normal physiological function of the nerve that does not rely upon an invasive and costly surgical procedure. The disclosed methods are able to “block” the transduction of both afferent and efferent signals from being transmitted via the trigeminal, facial, glossopharyngeal or vagus nerves. Such blockage of the transduction of signals on the nerve is achieved by a topical auricular anesthesia procedure, whereby a pharmaceutical composition is administered to the ear canal of a subject. It is the cutaneous auricular anesthesia of those nerves and their particular close proximity and relationship to their respective ganglia that allows for their modulation in function. It is that modulation of function which results in the modulation of expression of specific disease processes.

In an embodiment, the present disclosure provides a method for treating symptoms of a disease, which comprises topically administering to an ear canal of a subject a pharmaceutical composition, comprising: (i) an analgesic and (ii) an anesthetic. In an embodiment, the analgesic is at least one pyrazolone derivative selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone. In a preferred embodiment, the analgesic is antipyrine. In an embodiment, the anesthetic is at least one selected from the group consisting benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine, ropivacaine, trimecaine, and pharmaceutically acceptable derivatives thereof. In a preferred embodiment, the anesthetic is benzocaine.

An aspect of the invention provides for an otic pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative. In other aspects of the invention, the otic pharmaceutical composition further comprises (ii) at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃. An aspect of the invention further provides an otic pharmaceutical composition comprising at least 2 anesthetic compounds having Formula I as described herein. For example, the otic pharmaceutical composition can comprise the anesthetics tetracaine

and lidocaine

An aspect of the invention provides for a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction, the method comprising administering to an ear canal of a subject in need of such treatment an effective amount of a pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative, and/or (ii) at least one anesthetic comprising Formula I, and wherein said pharmaceutical composition is administered to the ear canal of the subject in a concentration sufficient to physiologically alter the activity of the subject's particular cranial nerve compared to the physiological activity of that particular cranial nerve in a subject not administered the pharmaceutical composition.

An aspect of the invention a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction, the method comprising administering to an ear canal of a subject in need of such treatment an effective amount of an otic pharmaceutical composition, wherein the pharmaceutical composition comprises at least 2 anesthetic compounds having Formula I as described herein. For example, the otic pharmaceutical composition can comprise the anesthetics tetracaine

and lidocaine

In one embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄ comprises H, NH₂,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃. In one embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄ comprises H, NH₂, or

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In one embodiment, the analgesic is at least one pyrazolone derivative selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone. In a preferred embodiment, the analgesic is antipyrine. In one embodiment, the anesthetic comprises benzocaine

chloroprocaine

cocaine

cyclomethycaine

dimethocaine

also referred to as larocaine), piperocaine

propoxycaine

procaine

also referred to as novocaine), proparacaine

also referred to as proxymetacaine), tetracaine

also referred to as amethocaine), articaine

bupivacaine

cinchocaine

also referred to as dibucaine), etidocaine

levobupivacaine

lidocaine

also referred to as lignocaine and xylocaine), mepivacaine

prilocaine

ropivacaine

farmocaine

trimecaine

bupivacaine, marcaine, a combination of the anesthetics listed herein, or pharmaceutically acceptable derivatives thereof. In another embodiment, the anesthetic is not benzocaine. In one embodiment, the anesthetic is lidocaine. In one embodiment, the anesthetic is tetracaine. In one embodiment, the anesthetic is tetracaine and lidocaine. In one embodiment, the anesthetic is lidocaine and bupivacaine.

In one embodiment, the invention is directed to a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve where auricular anesthesia is performed on the trigeminal nerve (cranial nerve 5), the facial nerve (cranial nerve 7), the glossopharyngeal nerve (cranial nerve 9), the vagus nerve (cranial nerve 10), the spinal accessory nerve (cranial nerve 11), the hypoglossal nerve (cranial nerve 12), or a combination thereof.

The diseases that are treatable by the disclosed methodology are numerous and described herein. Any disease that is associated with an organ or bodily tissue that is innervated by the particular nerve could potentially be treated by the present methods. Particular mention of the following diseases treatable by the present methods is made: asthma, neurogenic cough, globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease, and obesity. The present methods are also suitable for treating post-tonsillectomy or post-adenoidectomy pharyngeal pain, or oropharyngeal pain.

In one embodiment, the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, a metabolic-related affliction, an infection-related affliction, a skin-related affliction, a cell proliferation-related affliction, and/or a blood flow-related affliction.

In one embodiment, the neurology-psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-Traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Dysautonomia, Familial Intentional Tremor, Migraine pain, Autism Spectrum Disorder, Anxiety Headache, sleeplessness, Reticular Activating System (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent Pain, opiate withdrawal, Dysarthria, ADHD, Nonspecific hand tremor, Stuttering, cerebral palsy, Raynaud's Phenomenon, and excessive sweating, reflex sympathetic dystrophy, sensory processing disorder, and decreased libido. In one embodiment, the General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs, or shoulders; Joint Pain; Sciatica pain; Arthritis pain; Shingles Pain; Reflex Sympathetic Dystrophy pain; or a combination thereof. In one embodiment, a symptom of opiate withdrawal comprises Generalized Pain, Muscle Aches, Nausea, vomiting, Sweating, Diarrhea, or a combination thereof.

In one embodiment, the ear-nose-throat (ENT)-related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, ear pain, neck pain, Dry Eye Syndrome, Trigeminal Neuralgia pain, and Temporomandibular Joint Pain.

In one embodiment, the Gastroenterology/Urology (GU)-related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis, Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain, enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation, frequent urination, Prolonged Vaginal Bleeding, decreased renal blood flow, and chronic renal failure.

In one embodiment, the gastrointestinal (GI)-related affliction is at least one selected from the group consisting of: irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic, Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronic constipation, Chronic diarrhea, and Pancreatitis.

In one embodiment, the cardiac-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation, Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiac surgery derived cough, heart block, Atrial Contractions, Tachycardia, Congestive Heart Failure, premature atrial contraction, and atrial tachycardia.

In one embodiment, the pulmonary-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and Bronchospasm.

In one embodiment, the metabolic-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, hypercholesteremia, and insulin resistance.

In one embodiment, the infection-related affliction is at least one selected from the group consisting of: Herpes Simplex 1 infection, Herpes, Simplex 2 infection, and Varicella Zoster infection.

In one embodiment, the skin-related affliction is at least one selected from the group consisting of: facial flushing, facial blushing, alopecia areata, atopic dermatitis, chronic eczema, acne vulgaris, oily skin, rosacea, and morgellons disease.

In one embodiment, the cell proliferation-related affliction is at least one selected from the group consisting of: cancer and mastocytosis.

In one embodiment, the blood flow-related affliction is at least one selected from the group consisting of erectile dysfunction, open wound healing, and sickle cell disease.

In yet other embodiments, the diseases treatable by the disclosed methodology include, but are not limited to: cardiac diseases, paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope, postural orthostatic tachycardia syndrome (POTS), excessive gag reflex, esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain, esophageal neuralgia, gastritis, dyspepsia, gall bladder disease, colecistitis pain, abdominal pain, esophageal motility disorder or esophageal dysmotility, spastic colon, pancreatic pain or spasms, pediatric colic, rectal spasms and pain, bladder spasm (overactive bladder), interstitial cystitis, dysmenorrhea, premature labor, pelvic pain, chronic pelvic pain, chronic prostatitis pain, eclampsia, preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome, Cohn's disease, ulcerative colitis, reflux disease, gastritis, gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic, hepato-renal syndrome, appetite suppression, gall bladder pain, inflammation of the esophagus, inflammation of the stomach, inflammation of the colon, kidney pain (from stone, infection, or tumor), enuresis, dysuria, dyspareunia, encopresis, heavy flow periods, frequent urination, prolonged vaginal bleeding, inhibit erections, prevention of premature ejaculation, inhibit excessive sweating, ureteral spasms, menstrual cramps, uterine spasms, ovarian pain and spasms, fallopian tube pain and spasms, pediatric asthma, adult asthma, chronic obstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis, asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis, inflammation of the lung, emphysema, pleuritic chest pain, intercostal muscle pain, nerve pain, bronchospasm secondary to intubation and extubation, angina pectoris, cardiac vagal blockage, vasovagal reflex blockage, bradycardia, hypotension, orthostatic hypotension, hypertension, diabetes, shock, septic shock, reduction of blood sugar, inflammation of the pancreas, syncope secondary to vagal or cardiac reasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin, neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chronic laryngitis, post extubation and intubation laryngospasms, palatal myoclonus, post-tonsillectomy pain, snoring, allergic rhinitis, vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome, fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panic attacks, post-traumatic stress disorder, Tourette's syndrome, focal dystonia, tic doloreaux, bulimia, anxiety, depression, restless leg syndrome, dysautonomia, familial intentional tremor, migraines, autism spectrum, anxiety headaches, insomnia or sleep disorders, multiple sclerosis, modulation of the reticular activating system, peripheral neuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

Thus, the present method applies generally to the treatment of any disease, ailment, or bodily condition that may benefit from the “blockage” of the particular nerve function. That is, any condition that would benefit from the hampered ability of the nerve to transmit neurological signals are encompassed by the disclosed method.

In methods disclosed herein, the pharmaceutical composition is administered to the ear canal of a subject in a concentration sufficient to physiologically alter the activity of the subject's nerve compared to the physiological activity of a nerve in a subject not administered the pharmaceutical composition. Thus, the present pharmaceutical composition utilized in a method as disclosed, is able to disrupt the natural ability of the nerve to transmit neurological signals along its length. These signals, both afferent and efferent, are blocked or hampered by the present methods.

The amount of analgesic present in the pharmaceutical composition comprises from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100 mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg per mL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to 100 mg per mL, or 100 mg per mL. In some embodiments, the amount of analgesic present is from about 50 to 60 mg per mL, or about 54 mg per mL, or about 50 to 55 mg per mL, or about 55 to 60 mg per mL.

The amount of anesthetic present in the pharmaceutical composition comprises from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100 mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg per mL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to 100 mg per mL, or 100 mg per mL. In some embodiments, the amount of anesthetic present is from about 1 to 20 mg per mL, or about 1 to 15 mg per mL, or about 5 to 15 mg per mL, or about 10 to 20 mg per mL, or about 10 to 15 mg per mL, or about 14 mg per mL.

The total amount of the pharmaceutical composition administered to a patient during one dosage may comprise from about: 0.001 to 0.01 mL of solution, or 0.01 to 0.1 mL of solution, or 0.1 to 0.5 mL of solution, or 0.1 to 1 mL of solution, or 1 to 1.5 mL of solution, or 1.5 to 2 mL of solution, or 2 to 5 mL of solution, or 5 to 10 mL of solution. The administration may comprise using a “dropper” bottle that applies “drops” of solution to the patients ear canal during a typical dosage. Such administration may comprise 1 mL≈15-20 drops, 0.5 mL≈10 drops, 0.25 mL≈5 drops.

The pharmaceutical composition can comprise at least one anesthetic, at least one analgesic, or any combination thereof. For example, the composition can comprise one anesthetic, such as lidocaine; two anesthetics, such as lidocaine and bupivacaine; or an anesthetic and an analgesic, such as benzocaine and antipyrine.

The pharmaceutical composition can be provided in a solution comprising 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of one or more anesthetics. In one example, the composition comprises 4% lidocaine and 2% bupivacaine.

As used herein, unless otherwise expressly specified, all numbers such as those expressing values, ranges, amounts, or percentages may be read as if prefaced by the word “about,” even if the term does not expressly appear. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. Plural encompasses singular and vice versa; e.g., the singular forms “a,” “an,” and “the” include plural referents unless expressly and unequivocally limited to one referent.

In certain embodiments, the subject treated by the present methods does not have an ear infection. Furthermore, in certain embodiments, the subject treated by the present methods does not have an ear ache or is not experiencing ear pain.

In particular aspects, the present method is utilized on patients with ear infections. That is the present methods in certain embodiments specifically are utilized on patients with an external ear canal infection, with otalgia or with a middle ear infection, associated with or without purulence. Certain embodiments specifically utilize the methods on subjects experience an ear ache or ear pain. In these embodiments, a first step of method may comprise an ear examination by a treating physician to assure a patient does have an ear infection or is experiencing ear pain, or has a hole in the eardrum. It may consist of redness, middle ear effusion or swelling of the tissues of the external canal or distortion of the ear drum. In some aspects after ascertaining that the patient does indeed have an ear infection, whether it is in the ear drum, ear canal or middle ear, topical anesthesia in the form of Antipyrene/benzocaine dissolved in an excipient may be inserted in the ear canal in the form of an eardrop to reduce ear pain. This may also be done with lidocaine and tetracaine in a similar excipient of glycerine, with or without the presence of epinephrine. What is contraindicated is the usage of any topical anesthetic in the ear canal in the presence of an ear tube or pressure equalization tube or an active on going perforation.

The disclosed pharmaceutical compositions utilized in the present methods may comprise additional components such as: antibiotics, vasoconstrictors, glycerin, and acetic acid.

The pharmaceutical compositions may comprise any pharmaceutically acceptable carrier, or adjuvant, and may be formulated as: solutions, foams, gels, creams, pastes, lotions, emulsions, and combinations of the aforementioned.

The pharmaceutical composition may be administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, 10 to 20 times a day, or up to continuously throughout the day as needed. Further, in certain embodiments, the pharmaceutical composition is administered upon the onset of an asthma attack. In other embodiments, the pharmaceutical composition is administered upon a person feeling hungry. Some aspects of the methods entail administration of the pharmaceutical composition upon a patient feeling pain in their pharyngeal region. Certain embodiments contemplate not utilizing the taught compositions on patients that are experiencing ear pain, or that have an ear infection, or swelling in the ear associated with an ear infection. In these embodiments, the disclosed method of treating diseases associated with the vagus nerve may be immediately halted or stopped upon a patient developing ear pain.

A specifically preferred ailment to be treated by the disclosed method is the pharyngeal or oropharyngeal pain associated with a post-operative tonsillectomy or a post-operative adenoidectomy. These embodiments treat pain that patients feel after the aforementioned surgical procedures. In these embodiments, the pharmaceutical composition is applied to the ear canal of a subject that has had a tonsillectomy or adenoidectomy within: the preceding 168 hours (or 7 days), preceding 48 hours, preceding 24 hours, preceding 12 hours, preceding 4 hours, or immediately post-operation, prior to administering the pharmaceutical composition. Thus, the present method contemplates doctors prescribing the disclosed procedure and pharmaceutical composition to patients to utilize immediately upon feeling pain in the pharyngeal or oropharyngeal regions post-surgery.

Another particularly preferred ailment, or disease, to be treated by the disclosed method is asthma. In certain embodiments, acute asthma attacks are treated by the present methods. These embodiments involve administering the pharmaceutical composition to the ear canal of a subject that is presently experiencing an acute asthma attack. Further, these embodiments may comprise treatment of a subject that has experienced an asthma attack in the last 48, 24, 12, 6, or 1 hours. Thus, the methods taught herein may be used in conjunction with normal bronchodilators and corticosteroids for the treatment and management of a patient's asthma. The methods may be suitable for use on asthma patients experiencing a peak expiratory flow rate (PEFR) of 50 to 79% of the patient's normal peak flow readings, i.e. “the yellow zone” as classified by the American Lung Association. The methods are also suitable for use on a patient experiencing a peak expiratory flow rate of less than 50% of the patient's normal peak flow reading, i.e. “the red zone.” The methods can be utilized in conjunction with a rescue inhaler when a patient experiences a severe asthma attack. Consequently, in some embodiments, the present pharmaceutical composition is a component of a kit, wherein said kit comprises a rescue inhaler and a pharmaceutical composition comprising antipyrine and benzocaine. The kit is intended to be kept with a patient that is in danger of suffering a severe asthma attack. Further, in some embodiments, the pharmaceutical composition is part of an emergency first aid kit that is kept in school classrooms, for example. In these embodiments, teachers could utilize the present pharmaceutical composition in times of emergency, such as when a student suffers a severe asthma attack, but yet there is no rescue inhaler readily available.

The present methods are also suitable for use in treating chronic asthma. In these embodiments, patients utilize the disclosed compositions as taught in the present disclosure to prevent the onset of an acute asthma attack. In these methods, chronic asthma is managed by continuous use of the present methods. Thus, in certain embodiments, patients with asthma are administered the pharmaceutical compositions presented herein before the onset of an asthma attack. For example, certain embodiments of the present methods are effective at controlling asthma in patients that play sports. Often, patients suffering from asthma will experience a decreased ability to breathe upon physical exertion, which in some cases may lead to a severe asthma attack requiring the use of an inhaler. The present methods allow the treatment of a subject's ear canal with a pharmaceutical composition comprising antipyrine and benzocaine before the subject engages in playing a sport. In this manner, the present methods may be an effective therapy for patient's to utilize before engaging in physical activity, in order to reduce the likelihood of having an asthma attack.

Another particularly preferred condition, or disease, to be treated by the disclosed method is obesity. The present methods treat obesity by providing a mechanism to suppress a patient's appetite. By suppressing a patient's appetite, the present methods provide another tool for doctor's to utilize in managing a patient's weight. Thus, obesity may be treated by administering the taught pharmaceutical composition to a subject's ear canal. In some embodiments, subjects are treated with the taught pharmaceutical composition whenever the subjects experience a sensation of hunger. Further, some embodiments administer the disclosed pharmaceutical compositions to the subject's ear canal immediately before a meal is eaten, or 10 minutes to 60 minutes before a meal is eaten, or 20 to 60 minutes before a meal is eaten, or 30 to 60 minutes before a meal is eaten, or concurrently with the consumption of a food. Thus, in some aspects, the present method of auricular anesthesia of the vagus nerve is utilized on a patient within an hour prior to the patient eating any food. In this way, the patient's appetite is satiated and less food will be consumed. Further, some embodiments administer the disclosed pharmaceutical compositions to the subject's ear canal in the morning, preferably before the subject eats breakfast, thus providing an effective appetite suppressant that lasts until at least lunch.

In some embodiments, the present pharmaceutical compositions and treatment methodology are part of a comprehensive weight loss program that involves not only utilization of the pharmaceutical composition to curb a patient's appetite, but also may include a specific diet and exercise regime.

In some aspects, a person applying the topical pharmaceutical composition to a patient's ear canal should have good light, so as to get a superficial look into the patient's ear, so as to check for any gross obstructions, i.e. wax, skin, infection, purulence, or swelling. The person may gently pull the ear pinna outward and upward, so as to straighten out the ear canal. Ear drops comprising the taught pharmaceutical composition that have been previously warmed and are quite viscid should be applied to the posterior or back wall of the lateral ear opening. The drops should be applied very slowly and deliberately, one drop at a time, allowing for each drop to slowly migrate down the ear canal. The patient's head should be resting on its side on a flat soft surface for optimal application. The back wall of the canal and eardrum have a large portion of the vagal nerve fibers, and thus pointed application to this area is desired. In some aspects, children under 10 will require 4 to 8 drops per ear, while adults and children over 12 usually require 6 to 10 drops for anesthesia. In some embodiments, drops are always followed by a cotton ball in the lateral ear canal for about one hour to insure the maintenance of the medicine in the ear canal to provide the required topical anesthesia to the vagus nerve. After an hour the cotton may be removed.

The administration of a pharmaceutical composition to a patient's ear canal for the purpose of auricular anesthesia of the vagus nerve to treat a disease affected by vagus nerve physiological alteration is referred to in some embodiments as the “Crews Maneuver.” The Crews Maneuver of utilizing the ear canal as a conduit to anesthetizing the vagus nerve does not suffer from the drawbacks present in the art.

Aspects further comprise methods for ameliorating pain in a subject by administering to an ear canal of the subject afflicted with a distal pain an effective amount of a pharmaceutical composition comprising at least one anesthetic comprising Formula I described herein. In embodiments, a distal pain comprises a non-ear pain. The composition can further comprises at least one analgesic comprising a pyrazolone derivative. Still further, the pharmaceutical composition can comprise one or more of an antibiotic, a vasoconstrictor, glycerin, epinephrine, or acetic acid. In some embodiments, 2 or more anesthetics comprising formula I can be administered to a subject in an effective amount of a pharmaceutical composition.

In embodiments, the anesthetic can comprises benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine, ropivacaine, farmocaine, trimecaine, marcaine, bupivacaine, or a combination of the anesthetics listed herein.

In embodiments, the pyrazolone derivative is selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone.

In embodiments, the amount of anesthetic does not exceed 252 mg/day. In embodiments, the amount of analgesic administered does not exceed 972 mg/day.

In embodiments, the subject does not have an ear infection, ear pain, or a combination thereof.

Non-limiting examples of distal pain (i.e., non-ear pain) comprise post-tonsillectomy pharyngeal or oropharyngeal pain, post-adenoidectomy pharyngeal or oropharyngeal pain, laryngeal pain, migraine pain, anxiety headaches, peripheral neuropathy, neck and shoulder pain, general somatic afferent pain, neuromuscular pain, joint pain, sciatica pain, arthritis pain, shingles pain, reflex sympathetic dystrophy pain, general visceral afferent pain, post tonsillectomy pain, pharyngeal pain, laryngeal pain, neck pain, trigeminal neuralgia pain, temporomandibular joint pain, pelvic pain, chronic prostatitis pain, cystitis pain, kidney pain, gastritis pain, gall bladder pain, and pancreatitis pain.

Aspects are still further directed towards a method for treating a subject suffering from an affliction associated with a particular cranial nerve comprising administering to an ear canal of a subject an effective amount of a pharmaceutical composition comprising at least one anesthetic described herein. The composition can further comprises at least one analgesic comprising a pyrazolone derivative. Still further, the pharmaceutical composition can comprise one or more of an antibiotic, a vasoconstrictor, glycerin, epinephrine, or acetic acid.

In embodiments, the affliction comprises those described herein, such as a neurology-psychiatry-related affliction, ear-nose-throat (ENT)-related affliction, Gastroenterology/Urology (GU)-related affliction, gastrointestinal (GI)-related affliction, cardiac-related affliction, pulmonary-related affliction, metabolic-related affliction, infection-related affliction, skin-related affliction, cell proliferation-related affliction, or blood flow-related affliction.

These and other features, aspects, and advantages of embodiments of the present disclosure will become better understood with regard to the following description, claims, and accompanying drawings explained below.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

FIG. 1 is an illustration of the complex anatomy of the vagus nerve. The auricular branch is noted.

FIG. 2 is an illustration of the complex anatomy of the vagus nerve showing the innervation of the parasympathetic division on one side of the body.

FIG. 3 is an illustration of the anatomy of the facial nerve.

FIG. 4 is an illustration of the anatomy of the trigeminal nerve.

FIG. 5 is an illustration of the anatomy of the glossopharyngeal nerve.

FIG. 6 is an illustration of the glossopharyngeal nerve.

FIG. 7 is an illustration of the interior of a human ear. The ear canal is noted.

FIG. 8 is an illustration of the nerves of the Esophagus.

FIG. 9 is an illustration of cranial nerves C-3, 5, 7, and 10.

FIG. 10 is an illustration of the distribution of the hypoglossal nerve (cranial nerve 12).

FIG. 11 is an illustration of the anatomy of nerve innervations.

FIG. 12 is an illustration of the anatomy of nerve innervations of the sympathetic (red) and parasympathetic (blue) systems.

FIG. 13 is an illustration of the anatomy of nerve innervations of the sympathetic (blue) and parasympathetic (red) systems.

FIG. 14 is an illustration of the anatomy of nerve innervations, and preganglionic and ganglionic neurons.

FIG. 15 is an illustration of the anatomy of somatic (orange) and visceral (blue) motor fibers.

FIG. 16 is an illustration of the anatomy of nerve innervations, and preganglionic and ganglionic neurons.

FIG. 17 is an illustration of the anatomy of nerve innervations.

FIG. 18 is a map of cranial nerves in equines (top), canines (bottom), and felines (continuation page).

FIG. 19 is an illustration of brains of various vertebrate species.

DETAILED DESCRIPTION OF THE INVENTION

Detailed descriptions of one or more preferred embodiments are provided herein. It is to be understood, however, that the present disclosure may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present disclosure in any appropriate manner.

As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of an affliction or condition, or one or more symptoms thereof, prevent the advancement of conditions related to an affliction or condition, prevent the recurrence, development, or onset of one or more symptoms associated with an affliction or condition, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease, a stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

The term “in need thereof” refers to the need for symptomatic or asymptomatic relief from a condition such as, for example, cancer or a neurodegenerative disease. The subject in need thereof may or may not be undergoing treatment for conditions related to, for example, cancer or a neurodegenerative disease.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21^(st) Edition (University of the Sciences in Philadelphia, ed., Lippincott Williams & Wilkins 2005); and Handbook of Pharmaceutical Excipients, 7^(th) Edition (Raymond Rowe et al., ed., Pharmaceutical Press 2012); each hereby incorporated by reference in its entirety.

The terms “animal,” “subject,” and “patient” as used herein includes all members of the animal kingdom including, but not limited to, mammals, animals (e.g., cats, dogs, horses, swine, etc.) and humans.

Autonomic Nervous System.

The autonomic nervous system is divided into the sympathetic and parasympathetic components. The sympathetic nervous system prepares the body for stress and is called the “fight or flight” system. The parasympathetic system prepares the body for rest and is called the “rest and digest” or “vegetative” system.

The sympathetic nervous system is one of the two main divisions of the autonomic nervous system; the other being the parasympathetic nervous system. Sympathetic nervous system can be modulated or significantly affected by the usage of auricular anesthesia to the external auditory canal. Auricular anesthesia to the external auditory canal can modulate the vagus and glossopharyngeal nerves, which have direct connections to the sympathetic chain or nervous system (see FIG. 12 , FIG. 13 ; see also FIG. 1 and FIG. 5 ). The primary process of the sympathetic nervous system is to stimulate the body's flight or fight response. It is however constantly active at a basic level to maintain homeostasis. It works as a compliment in intimate conjunction with the parasympathetic nervous system by direct neural communication.

There are two kinds of neurons involved in the transmission of any signal through the sympathetic nervous system: preganglionic or post-ganglionic. The shorter preganglionic neurons originate in the thoracolumbar region of the spinal cord (levels T1 to L2 specifically) to travel to a ganglion often one of the paravertebral ganglion where they synapse with a postganglionic neuron. From there, the long post-ganglionic neuron extends across most of the body. The sympathetic nerves arise from near the middle of the spinal cord in the intermediolateral nucleus of the lateral gray column, beginning at the first thoracic vertebrae of the vertebral column and are thought to extend to the second or third lumbar vertebrae. Axons of these nerves leave the spinal cord through the anterior root. They pass near the spinal sensory ganglion and they enter the anterior rami of the spinal nerves. However, unlike somatic innervation, they quickly separate out through white rami connectors that connect to either the paravertebral or the prevertebral ganglia extending alongside the spinal column. Presynaptic nerves or axons terminating either of the paravertebral ganglia or the prevertebral ganglia. In all cases, the axon enters the paravertebral ganglia at the level of its originating spinal nerve. After this it can either synapse in this ganglion, ascend to a more superior, or descend to a more inferior paravertebral ganglion and synapse there, or it can descend to a prevertebral ganglion and synapse there with the post-synaptic cell. Post-synaptic cell then goes on to innervate the target and effector, i.e. gland, smooth muscle, etc. Notable exceptions are the routes for innervation of the suprarenal adrenal medulla. In this case, the presynaptic neurons pass through the paravertebral ganglia onto through the prevertebral ganglia and then synapse directly with the suprarenal tissue. Auricular anesthesia to the vagus nerve can send signals to the paravertebral ganglia and affect neural transmission and thus affect sympathetic outflow to various organs, muscles, blood vessels, glands, skin, and nerves thus affecting disease processes.

The sympathetic nervous system is involved in hundreds of disease processes including the following: chronic fatigue syndrome, fibromyalgia, post-traumatic stress disorder, restless leg, anxiety, dysautonomia, hand tremors, migraine headaches, and muscle diseases such as multiple sclerosis, cerebral palsy, and Parkinson disease. Other diseases such as peripheral neuropathies, arthritis, reflex sympathetic dystrophy, muscle aches, sweating, orthostatic hypotension, postural orthostatic tachycardia syndrome, vasovagal reflex, cardiac arrhythmias, hypertension, diabetes, elevated blood sugar, elevated cholesterol, irritable bowel disease, irritable bowel syndrome, chronic constipation, ulcerative colitis, eclampsia, preeclampsia, HELLP syndrome, premature ejaculation, supraventricular tachycardia, and congestive heart failure can all be affected by an overactive sympathetic nervous system. Modulation of this system can be accomplished by directly modulating the parasympathetic nervous system via the auricular branch of the vagus nerve and the glossopharyngeal nerve and its intimate connections with the superior cervical sympathetic ganglion with its connections to the rest of the sympathetic nervous system, please see pending figures. It should also be noted that functions of the sympathetic nervous system also include dilation of pupils, increased in drying of the eyes, increased drying of the nose and the mouth, increasing the heart rate and force of contraction, dilation of bronchials, dilation of skeletal muscles, dilation of blood vessels going to the brain, decreasing blood flow to the kidney, decreasing blood flow to the gastrointestinal tract, increasing activation of sweat glands inhibiting peristalsis, increasing levels of renin, increasing levels of cholesterol and triglycerides, increasing levels of blood pressure, and promoting ignition for ejaculation.

The present invention provides for a method of treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction. In one embodiment, the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction. In one embodiment, the neurology-psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-Traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Dysautonomia, Familial Intentional Tremor, Migraine pain, Autism Spectrum Disorder, Anxiety Headache, sleeplessness, Reticular Activating System (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent Pain, opiate withdrawal, Dysarthria, ADHD, Nonspecific hand tremor, Stuttering, cerebral palsy, Raynaud's Phenomenon, and excessive sweating. In one embodiment, the General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs, or shoulders; Joint Pain; Sciatica pain; Arthritis pain; Shingles Pain; Reflex Sympathetic Dystrophy pain; or a combination thereof. In one embodiment, a symptom of opiate withdrawal comprises Generalized Pain, Muscle Aches, Nausea, vomiting, Sweating, Diarrhea, or a combination thereof. In one embodiment, the ear-nose-throat (ENT)-related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, ear pain, neck pain, Dry Eye Syndrome, Trigeminal Neuralgia pain, and Temporomandibular Joint Pain. In one embodiment, the Gastroenterology/Urology (GU)-related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis, Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain, enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation, frequent urination, Prolonged Vaginal Bleeding, and decreased renal blood flow. In one embodiment, the gastrointestinal (GI)-related affliction is at least one selected from the group consisting of: irritable bowel syndrome (MS), ulcerative colitis, acid reflux, Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic, Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronic constipation, Chronic diarrhea, and Pancreatitis. In one embodiment, the cardiac-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation, Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiac surgery derived cough, heart block, Atrial Contractions, Tachycardia, and Congestive Heart Failure. In one embodiment, the pulmonary-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and Bronchospasm. In one embodiment, the metabolic-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, and hypercholesteremia.

General visceral and afferent fibers conduct sensory impulses usually pain and reflex sensations from the viscera, glands, and blood vessels to the central nervous system. They are considered to be part of the visceral nervous system not the autonomic nervous system. However, unlike the efferent fibers of the autonomic nervous system the afferent fibers are not classified as either sympathetic or parasympathetic. General visceral afferent create referred pain to activating general somatic afferent fibers where the two meet in the posterior horn of the spinal cord. The cranial nerves that contain general visceral afferent fibers include the facial nerve, the glossopharyngeal nerve, and the vagus nerve all of which innervate the external auditory canal. General visceral afferent referred pain can be modulated by auricular anesthesia to these cranial nerves as they provide sensory innervation to specific areas of the external auditory canal. Topical anesthesia to these areas can modulate general visceral afferent signals from the body back to the central nervous system.

General somatic afferent fibers (GSA or somatic sensory nerves) afferent fibers arrive from cells in the spinal ganglia and are found in all the spinal nerves, except occasionally the first cervical, and conduct impulses of pain, touch, and temperature from the surface of the body through the posterior roots of the spinal cord and impulses of muscle sense, tendon sense, and joint sense from the deeper structures. General somatic afferent fibers travel through the sympathetic chain into the spinal nerve into the dorsal root ganglion into the dorsal root and into the spinal cord. It can travel up the spinal cord to the central nervous system to the thalamic level and then onto the cerebrum where they can be involved in a reflex arch involving visceral motor and somatic motor nerves which also travel from the ventral root back through the sympathetic chain to their respectful organs. FIGS. 12-13 . It is not known at this time whether the modulation of the sympathetic paravertebral and prevertebral nervous system modulates pain at the ganglion or at the thalamic level at this time. Without being bound by theory, general somatic afferent pain and general visceral afferent pain can be modulated through auricular anesthesia topically applied to the external canal modulating the vagus nerve and its attachments to the sympathetic nervous system.

Vertebrate anatomy has many common neurologic anatomic and physiologic aspects. There is no reason to preclude the usage of topical anesthesia or auricular modulation of the external auditory canal for purposes of modulating disease via cranial nerves and the sympathetic nervous system in other vertebrate species namely primates, felines, canines, bovines, and rodent species. Without being bound by theory, other vertebrate species can also benefit from the treatment of specific cranial nerve-associated diseases by way of auricular modulation of the autonomic nervous system. The method comprises topically administering to an ear canal of a vertebrate subject a pharmaceutical composition comprising: i. an analgesic, and/or ii. an anesthetic to the external auditory canal.

Cranial Nerves.

The vagus nerve, also known as cranial nerve X, is the tenth of twelve paired cranial nerves and is the longest of the cranial nerves. Upon leaving the medulla between the medullary pyramid and the inferior cerebellar peduncle, it extends through the jugular foramen, then passes into the carotid sheath between the internal carotid artery and the internal jugular vein down below the head, to the neck, chest and abdomen, where it contributes to the innervation of the viscera. The anatomy of the vagus nerve is illustrated in FIGS. 1 and 2 .

Upon exiting the jugular foramen, the vagus nerve forms the jugular ganglion and the ganglion nodosum or the superior and inferior vagal ganglion. The jugular ganglion is joined by filaments from the petrous ganglion of the glossopharyngeal nerve. The auricular branch of the vagus nerve also has connections from the jugular ganglion of ten and the petrous ganglion of the glossopharyngeal nerve as it enters the mastoid canaliculus from the lateral wall of the jugular fossa. Brushing the temporal bone, the auricular branch of vagas exits the tympanomastoid fissure and divides into two branches; one joins the post-auricular nerve and the other is distributed to the skin of the back of the ear and to the posterior external acoustic meatus.

The vagus nerve conveys sensory information about the state of the body's organs to the central nervous system. Approximately 80% of the nerve fibers in the vagus nerve are afferent, or sensory nerves, communicating the state of the viscera to the brain, while the remaining 20% are efferent, or functional nerves.

The vagus nerve is responsible for regulating a host of bodily functions, including, but not limited to, breathing, speech, sweating, facilitating in keeping the larynx open during breathing, monitoring and regulating heartbeat, and digestion of food in the stomach, along with a host of other physiological functions.

Consequently, manipulation of the vagus nerve and subsequent alteration of its normal physiological function may have profound effects upon a wide range of human ailments that are associated with vagus nerve regulation. However, the present procedures available in the art for altering the function of the vagus nerve are highly invasive. These current procedures often rely upon the implantation of artificial mechanical devices into the body of a patient. Besides being highly invasive surgical procedures, these methods are very costly.

For instance, the United States Food and Drug Administration approved a procedure called vagus nerve stimulation (VNS) in the late 1990s for the treatment of partial onset epilepsy. VNS is performed as a surgical procedure to install a pacemaker-like device into a subject suffering from epileptic seizures. The device, implanted inside a patient's neck area, is used to send mild electrical impulses through the vagus nerve. The device is battery operated, and has an electrical pulse generator. After it is implanted, electrodes with insulated plastic are run into the vagus nerve from under the skin on the patient's neck. The pulse is set to operate alternately, by turning on every few seconds and then turning off.

Researchers have also begun to investigate the possibility of utilizing these pacemaker-like devices in the stomach of obese patients to block the function of the vagus nerve, in order to suppress appetite. Again, these procedures are highly invasive and involve the implantation of artificial devices into the body of a patient.

Some surgeons have even performed vagotomy procedures to treat obesity. In these procedures, the surgeon completely severs a patient's vagus nerve. While these procedures successfully allowed the subjects to lose weight, it is apparent that such an invasive and permanent surgical procedure is problematic for many patients.

Cranial nerve seven or the facial nerve is one of the twelve paired cranial nerves (see FIG. 3 ). It is so named because its main function is to supply motor innervation to the muscles of the face. Other muscles it innervates are the platysma, the posterior belly of the digastric, and the stapedius muscle. The sensory and parasympathetic portion of the facial nerve travels in the nervus intermedius and supplies the following components: (1) taste to the anterior two-thirds of the tongue; (2) secretory and vasomotor fibers to the lacrimal gland, the mucus glands of the nose and sinuses, mouth, and the submandibular and sublingual salivary glands; and (3) cutaneous sensory impulses from the external auditory meatus and regions of the back of the ear. It is also thought that a parasympathetic impulse from the nervus intermedius, to the sphenopalatine ganglion, to the mucosa and submucosa of the nose and paranasal sinuses determines their venous capacitance and level of congestion.

The parasympathetic portion of the seventh cranial nerve takes its origin in the nucleus salivatorius in the brain stem and enters the interior acoustic meatus separate from the motor division of the facial nerve. It combines with the facial nerve proximal to the geniculate ganglion. The fibers leave the geniculate ganglion through the great superficial petrosal nerve and are joined by the large deep petrosal nerve to form the vidian nerve, or the nerve of the pterygoid canal, where together they move forward to synapse in the sphenopalatine ganglion. There they provide parasympathetic innervation to the eye, nose, sinus, palate, pharynx, and salivary glands. The geniculate ganglion receives general somatic afferent fibers from the external auditory canal via the auricular branch of the vagus nerve and its connection to the seventh cranial nerve. General somatic sensory afferent fibers synapse in the geniculate ganglion.

The trigeminal nerve or the fifth cranial nerve is the fifth of twelve paired cranial nerves and is the largest of all the cranial nerves (see FIG. 4 ). It is the great sensory nerve of the skin of the face, scalp, ear canal, the mucus membranes and other internal structures of the head. It also has functions as motor innervation to the muscles of mastication and contains proprioceptive fibers. It further carries sensory innervation from the dura of the brain with its various branches. The fifth cranial nerve is quite extensive. The main sensory nucleus extends from the pons to the upper spinal cord. The nucleus receives its afferent fibers from the semi-lunar ganglion, also known as the Trigeminal ganglion or the Gasserian ganglion. The Trigeminal ganglion contains the cell bodies of the sensory fibers for its three main divisions. It receives three large sensory division: the ophthalmic, maxillary, and mandibular divisions. The sensory root fibers leave the ganglion posteriorly to pass their insertion into the pons.

The glossopharyngeal nerve, also known as the ninth cranial nerve, is the ninth of twelve paracranial nerves that is known as the tympanic nerve and has both sensory and secretory fibers (see FIGS. 5 and 6 ). The nerve is a mixed sensory and motor nerve. The sensory component consists of somatic afferent fibers supplying sensation to the mucus membranes of the pharynx and tonsillar region and back of the tongue. The superficial origin of the glossopharyngeal nerve from the brain stem is by three or four rootlets in the groove between the olive and the inferior peduncle. It exits the skull through the jugular foramen and runs anteriorly between the internal carotid artery and the internal jugular vein. Upon exiting the jugular foramen, it forms a pair of ganglionic swellings: the superior or jugular ganglion, and the inferior or petrosal ganglion. The ganglion contains cell bodies of the sensory fibers of the nerve. The ninth nerve communicates with the vagus nerve or the tenth cranial nerve, the facial nerve, and the sympathetic ganglion. The glossopharyngeal nerve has five distinct general functions: (1) motor (special visceral efferent) supplies the stylopharyngeus muscle; (2) visceral motor (general visceral efferent) provides parasympathetic innervation of the parotid gland; (3) visceral sensory (general visceral afferent) carries visceral sensory information from the carotid sinus and carotid body; (4) general sensory (general somatic efferent) provides general sensory information from the skin of the external ear, internal surface of the tympanic membrane, upper pharynx, and posterior one-third of the tongue; and (5) special sensory (special afferent) provides taste sensation from the posterior one-third of the tongue, including circumvallate papillae.

The accessory nerve or the spinal accessory nerve is cranial nerve 11. The cranial nerve controls the sternocleidomastoid muscle and the trapezius muscle. The sternocleidomastoid muscle tilts and rotates the head while the trapezius muscle has several factors on the scapula including shoulder elevation and abduction of the arm. Range of motion and strength testing in the neck and shoulders can be measured during a neurological exam to assess the function of the spinal accessory nerve. Limited range of motion or poor muscle strength indicate damage to the spinal accessory nerve. This can be the result from a variety of causes of the cranial nerves. The spinal accessory nerve exits the cranium through a specialized hole or foramen. The nerve originates in the majority of individuals in the neurons situated in the upper spinal cord. From there, the fibers enter the foramen magnum and course along the inner wall of the skull toward the jugular foramen through which it exits the skull with the glossopharyngeal (or 9th cranial nerve) and the vagus nerve (or the 10th cranial nerve) owing to is peculiar course the spinal accessory nerve is notable for being the only cranial nerve to both enter and exit the skull (FIG. 1 , FIG. 2 , and FIG. 5 ). Once the nerve exits the jugular foramen, it crosses the internal jugular vein around the level of the posterior belly of the digastric muscle. It courses on to innervate the trapezius and sternocleidomastoid muscles. Function of the spinal accessory nerve is special visceral efferent or innervation and function of the motor control of the sternocleidomastoid and trapezius muscle. Abnormalities of the spinal accessory nerve can cause spasm of these two muscles along with fasciculation and weakness or aberrations in head, neck, shoulder, and arm movements and range of motion. The spinal accessory nerve is intimately connected to the vagus nerve that is the superior and inferior ganglion of the vagus nerve. Auricular anesthesia of the vagus nerve directly modulates electrical input and function of the spinal accessory nerve (see FIG. 5 ).

The hypoglossal nerve is the 12th cranial nerve, and innervates the muscles of the tongue. The nerve arises along with the other cranial nerves in the brain stem. The nerve exits the skull base in the posterior fossa through the hypoglossal canal. As it exits the skull, it gives off a small meningeal branch and picks up a branch from the anterior ramus of C1. It follows in near proximity to the vagus nerve and the spinal position of the accessory nerve and it follows behind the vagus nerve and passes between the internal carotid artery and the interior jugular vein lying on the carotid sheath. It passes deep into the posterior belly of the digastric muscle in the submandibular region. It passes lateral to the hyoglossus muscle in the inferior laryngeal nerve to reach and efferently innervate the tongue. It is intimately involved in speech as it innervates the tongue. It innervates intrinsic and extrinsic muscles of the tongue and is characterized as general somatic efferent nerve type. It can be modulated by indirect modulation or anesthesia to the vagus nerve, which directly communicates to the hypoglossal nerve (see FIG. 1 and FIG. 5 ). The hypoglossal nerve is involved in speech, as well as swallowing to clear the mouth of saliva and other involuntary activities completed by the tongue. Most functions are voluntary. Voluntary functions require conscious thought and nerve pathways occur in the corticobulbar region of the spinal cord. The hypoglossal nucleus is supplied by innervation from the reticular formation by which it is involved in several reflexive or automatic motions and in aiding unconscious movement required upon engaging in speech and articulation. Modulation of signals to the hypoglossal nerve via the 10th cranial nerve may have profound effects on the improvement of articulation, speech, swallowing, and posterior fossa headaches.

Thus, there is a great need in the medical community for methods of treating vagus and other cranial nerve associated diseases that are not dependent upon altering the function of the vagus nerve or other cranial nerves through invasive surgical procedures or artificial devices. Specifically, there is a great need in the art for procedures to alter the function of the vagus and other cranial nerves that are non-invasive, safe, effective, and economical

Disrupting Transduction of Neurological Signals Along the Cranial Nerves.

The present invention provides for methods of treating a variety of diseases disclosed herein that comprises performing auricular anesthesia (e.g., topical anesthesia) of the external auditory canal for the purposes of anesthetizing cranial nerves 5, 7, 9, 10, 11, and/or 12. The present invention also provides for methods of treating a variety of diseases disclosed herein that comprises performing auricular anesthesia (e.g., topical anesthesia) of the sympathetic and/or parasympathetic nervous system(s). The present invention further for methods of treating a variety of diseases disclosed herein that comprises performing auricular anesthesia of general visceral afferent, general somatic afferent, general visceral efferent, and/or general somatic efferent nerves. In some embodiments, auricular anesthesia is performed in a variety of vertebrate species including but not limited to species such as humans, horses, cows, pigs, dogs, cats, etc. In some embodiments, auricular anesthesia is performed by way of administering a combination of lidocaine and tetracaine combined in solution with an excipient glycerin with and without the presents of epinephrine. Antipyrine and Benzocaine can also be used in conducting auricular anesthesia of the external auditory canal for the purpose of treating diseases (see Examples herein). Glycerin is a usp based substance of the excipient. Tetracaine may also be administered without epinephrine to obtain similar results. Other excipients will also be utilized to carry the topical anesthetic or topical analgesic. In one embodiment, the present disclosure provides a method for treating symptoms of a disease which comprises topically administering to an ear canal of a subject a pharmaceutical composition comprising of an anesthetic and another anesthetic. In some embodiments, an analgesic with an anesthetic may also be utilized. This would be a separate eardrop in and of itself. In one embodiment, the analgesic is antipyrine, but could also consist of other known analgesics. In an embodiment, the anesthetic is at least one of a selected group consisting of an amide or an ester compound discussed herein.

The tenth cranial nerve (vagus nerve) is associated with numerous bodily organs and alteration of its normal physiological function can have profound effects on a host of human ailments. That is, by “blocking” or “disrupting” or “numbing” the conduction of neurological signals in the particular nerve, one is able to influence a host of organs that are innervated by that nerve. Consequently, blocking the transduction of signals transmitted along the nerve, whether those signals are afferent or efferent in nature, will alter the normal physiological response of various organs and tissues. This, in turn, can have profound implications for treating a variety of diseases, or ailments that are associated with human organs and tissues that are innervated by the particular nerve.

Auricular anesthesia of the cutaneous portion of the seventh cranial nerve (facial nerve) carry signals back to the geniculate ganglion where parasympathetic fibers and sensory fibers are anesthetized, blocked, or otherwise modulated. Anesthesia of the geniculate ganglion and its connection to the Sphenopalatine ganglion serve to modulate or block transduction of efferent signals through the facial nerve. This can profoundly affect disease processes such as, but not limited to, allergic rhinitis, vasomotor rhinitis, inflammatory nasal polyposis, chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, and rhinitis in all forms.

The sensory aspect of the fifth cranial nerve (trigeminal nerve) deals with information from the dura, the mucus membranes of the eyes, the mucus membranes of the nose and sinuses, the skin of the external auditory canal eardrum. Auricular anesthesia of the skin of the ear canal then signals to the trigeminal ganglion via the auriculotemporal branch of the mandibular division of the trigeminal nerve. Modulation of afferent signals through the trigeminal ganglion has profound effects on multiple disease processes. Modulating those afferent signals from the dura, the eye, the nose and sinuses leads to modulation of various disease processes. Manipulation of dural signals that pass through the ophthalmic, maxillary, and mandibular divisions have profound effects in the treatments of headaches and migraine headaches. Manipulation or modulation or blockage of afferent signals from the ophthalmic and maxillary divisions of the trigeminal nerve will result in modulated efferent signals from the motor division of the seventh cranial nerve that deal with allergic rhinitis, vasomotor rhinitis, all forms of rhinitis, inflammatory nasal polyposis, chronic sinusitis, chronic nasal congestion, allergic conjunctivitis and sneezing.

Auricular anesthesia of the cutaneous portion of the ninth cranial nerve (glossopharyngeal nerve) and its proximity to the petrous ganglion and its connection to the seventh cranial nerve and tenth cranial nerve can have profound effect on certain disease processes. Because of neural connections between the glossopharyngeal nerve and those of the seventh and tenth cranial nerves, disease processes specific to those nerves may also be modulated. Diseases specific to the glossopharyngeal nerve that may be affected by topical auricular anesthesia include, but are not limited to, pharyngeal pain, post tonsillectomy pain, sneezing, and parotid salivation.

Thus, several embodiments of the present invention comprise a method that blocks the transduction of efferent signals via the vagus, trigeminal, facial, or glossopharyngeal nerves. Another embodiment of the disclosure blocks the afferent transduction of signals via the vagus, trigeminal, facial, or glossopharyngeal nerves. The present disclosure also provides a methodology by which both the afferent and efferent signal transduction via the vagus, trigeminal, facial, or glossopharyngeal nerves is blocked.

In one embodiment, the invention provides for a method of treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction, the method comprising administering to an ear canal of a subject in need of such treatment an effective amount of a pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative, and (ii) at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃, and wherein said pharmaceutical composition is administered to the ear canal of the subject in a concentration sufficient to physiologically alter the activity of the subject's particular cranial nerve compared to the physiological activity of that particular cranial nerve in a subject not administered the pharmaceutical composition. In one embodiment, the particular cranial nerve is the trigeminal nerve, the facial nerve, the glossopharyngeal nerve, the accessory nerve, the hypoglossal nerve, the vagus nerve, or a combination thereof.

Pharmaceutical Compositions.

The methods of the present disclosure utilize the application of a pharmaceutical composition to the ear canal of subject in need of such treatment. The ear canal is illustrated in FIG. 7 . The pharmaceutical compositions comprise an analgesic and an anesthetic, one or more analgesics, or one or more anesthetics. For example, the composition can comprise one anesthetic, such as lidocaine; two anesthetics, such as lidocaine and bupivacaine; or an anesthetic and an analgesic, such as benzocaine and antipyrine.

The analgesic present in embodiments of the disclosure are pyrazolone (C₃H₄N₂O) derivatives. The molecular structure of 3-pyrazolone is as follows:

Derivatives of the isomeric form 5-pyrazolone are also encompassed by the disclosure.

Particular embodiments of the present methods utilize antipyrine as the pyrazolone derivative. Antipyrine (C₁₁H₁₂N₂O) is also referred to as phenazone. The molecular structure of antipyrine is as follows:

In one embodiment, the methods and pharmaceutical compositions comprise at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In another embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄ comprises H, NH₂,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In one embodiment, the anesthetic comprises

or a combination thereof.

In one embodiment, the anesthetic comprises benzocaine

chloroprocaine

cocaine

cyclomethycaine

dimethocaine

also referred to as larocaine), piperocaine

propoxycaine

procaine

also referred to as novocaine), proparacaine

also referred to as proxymetacaine), tetracaine

also referred to as amethocaine), articaine

bupivacaine

cinchocaine

also referred to as dibucaine), etidocaine

levobupivacaine

lidocaine

also referred to as lignocaine and xylocaine), mepivacaine

prilocaine

ropivacaine

farmocaine

trimecaine

a combination of the anesthetics listed herein, or pharmaceutically acceptable derivatives thereof. In another embodiment, the anesthetic is not benzocaine.

In one embodiment, the anesthetic is lidocaine.

In one embodiment, the anesthetic is tetracaine.

In one embodiment, the anesthetic is tetracaine and lidocaine.

In one embodiment, the anesthetic is lidocaine and bupivacaine.

The anesthetic present in some embodiments of the disclosure are ester based anesthetics. In a particular embodiment, the anesthetic is benzocaine (C₉H₁₁NO₂), the molecular formula of which is as follows:

In another embodiment, the anesthetic is not benzocaine.

Further embodiments of the method utilize amide based anesthetics.

In a preferred embodiment of the present methods, the disclosed pharmaceutical compositions comprise antipyrine as the analgesic and benzocaine as the anesthetic.

In some embodiments, the disclosed pharmaceutical compositions comprise antipyrine as the analgesic and tetracaine and/or lidocaine as the anesthetic. In some embodiments, the disclosed pharmaceutical compositions comprise tetracaine and lidocaine as the anesthetic.

In one embodiment, the invention is directed to an otic pharmaceutical composition. In various embodiments, the otic pharmaceutical composition comprises (i) at least one analgesic comprising a pyrazolone derivative, and/or (ii) at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃, and wherein the analgesic is present in the pharmaceutical composition in a concentration of from about 50 to about 60 mg per mL, and wherein the anesthetic is present in the pharmaceutical composition in a concentration of from about 10 to about 20 mg per mL.

In one embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄ comprises H, NH₂, or

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In some embodiments, the otic pharmaceutical composition further comprises an antibiotic, a vasoconstrictor, glycerin, epinephrine, acetic acid, or a combination thereof. In some embodiments, the anesthetic comprises lidocaine, tetracaine, benzocaine, or a combination thereof. In some embodiments, the anesthetic is not benzocaine. In further embodiments, the anesthetic comprises lidocaine, tetracaine, or a combination thereof.

In one embodiment, the pyrazolone derivative of the otic pharmaceutical composition comprises ampyrone, dipyrone, antipyrine, aminopyrine, or propyphenazone. In some embodiments, the analgesic is antipyrine.

The pharmaceutical compositions may be formulated in a host of ways, including, but not limited to, the following: solutions, foams, gels, creams, pastes, lotions, emulsions, and combinations of the aforementioned.

Furthermore, the present disclosure contemplates that active ingredients of the pharmaceutical composition, such as antipyrine and benzocaine, may be infused into material that is then placed into a patient's ear canal. For instance, cotton gauze material could be composed to contain the present pharmaceutical composition, said gauze providing a convenient application method by which to expose the ear canal to the present pharmaceutical composition.

In one embodiment, an otic pharmaceutical composition is administered to an ear canal of a subject in need of such treatment, wherein the subject is a vertebrate species that includes but is not limited to a human, horse, cow, pig, dog, cat, etc. In some embodiments, the otic pharmaceutical composition comprises a topical anesthetic alone or in combination with other topical anesthetics with or without analgesics. In one embodiment, the analgesic is antipyrine. In another embodiment, the anesthetic is at least one selected from the group consisting of benzocaine, formacaine, cocaine, and cyclomethycaine. In other embodiments, the anesthetic comprises tetracaine and/or lidocaine. In some embodiments, the otic pharmaceutical composition further comprises the presence or absence of epinephrine, suspended in solution of various pharmaceutical carriers. The otic pharmaceutical composition is subsequently administered to the ear canal for the desired effect.

Anatomical Site of Application of the Pharmaceutical Composition

The invention provides for methods for treating a variety of diseases that comprises performing topical auricular anesthesia of the external auditory canal for the purposes of anesthetizing cranial nerves 5, 7, 9, 10, 11, and 12, along with anesthetizing the parasympathetic nervous system, and/or the sympathetic nervous system. In one embodiment, the invention provides for treating a variety of diseases that comprises performing topical auricular anesthesia of the autonomic nervous system. In one embodiment, auricular anesthesia is performed on the trigeminal nerve (cranial nerve 5), the facial nerve (cranial nerve 7), the glossopharyngeal nerve (cranial nerve 9), the vagus nerve (cranial nerve 10), the spinal accessory nerve (cranial nerve 11), the hypoglossal nerve (cranial nerve 12), or a combination thereof. The invention further provides for modulation of the general somatic nervous system and the general visceral nervous system by administering an otic pharmaceutical composition comprising one or more anesthetics (such as lidocaine and/or tetracaine) in solution with a pharmaceutical carrier (such as an excipient) glycerine, and with or without epinephrine. In some embodiments, the otic pharmaceutical composition further comprises an analgesic, such as a pyrazolone derivative. In some embodiments, the pyrazolone derivative is antipyrene.

The present method contemplates applying the disclosed pharmaceutical composition to the ear canal of a patient. It has been found that the ear canal serves as a convenient point in the human anatomy in which to apply the present pharmaceutical composition and achieve disruption of neurological signals along the vagus or other cranial nerves. That is, by placing a pharmaceutical composition, as described herein, into the ear canal of a patient, it has been discovered that the body will absorb the composition and the vagus or other cranial nerve will be “blocked,” such that the normal physiological function of the nerve will be altered. The present methodology of utilizing the ear canal as a conduit to anesthetizing the particular nerve does not suffer from the drawbacks present in the prior art.

The present methods of applying a pharmaceutical composition as described are not invasive and do not pose the risks associated with surgical procedures. Furthermore, the present methods do not rely upon inserting artificial devices into the body of patient. It is evident that the present methods represent a significant advancement over the state of the art, as the disclosed non-invasive procedure is able to alter the function of the vagus or other cranial nerve without artificial devices or surgery. The present methods are also economical and would therefore provide access to treatment to the vast majority of a population.

The presently disclosed embodiments of a method of blocking signal transduction upon the vagus nerve will now be further elaborated upon by reference to the following examples. In each of these examples, the disclosed method was able to successfully treat a human disease, or ailment, that was associated with a particular cranial nerve. Without being bound by theory, the methods are also useful to treat a disease or ailment associated with a particular cranial nerve in a variety of vertebrate species including but not limited to horses, cows, pigs, dogs, cats, etc. Conditions treated in the examples disclosed herein were able to be controlled to a clinically effective degree by the disclosed method of performing auricular anesthesia on the vagus or other cranial nerve, or by performing auricular anesthesia of the autonomic nervous system, i.e. referred to as the “Crews Maneuver.” In one embodiment, the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction. In one embodiment, the neurology-psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-Traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Dysautonomia, Familial Intentional Tremor, Migraine pain, Autism Spectrum Disorder, Anxiety Headache, sleeplessness, Reticular Activating System (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent Pain, opiate withdrawal, Dysarthria, ADHD, Nonspecific hand tremor, Stuttering, cerebral palsy, Raynaud's Phenomenon, and excessive sweating. In one embodiment, the General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs, or shoulders; Joint Pain; Sciatica pain; Arthritis pain; Shingles Pain; Reflex Sympathetic Dystrophy pain; or a combination thereof. In one embodiment, a symptom of opiate withdrawal comprises Generalized Pain, Muscle Aches, Nausea, vomiting, Sweating, Diarrhea, or a combination thereof. In one embodiment, the ear-nose-throat (ENT)-related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, ear pain, neck pain, Dry Eye Syndrome, Trigeminal Neuralgia pain, and Temporomandibular Joint Pain. In one embodiment, the Gastroenterology/Urology (GU)-related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis, Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain, enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation, frequent urination, Prolonged Vaginal Bleeding, and decreased renal blood flow. In one embodiment, the gastrointestinal (GI)-related affliction is at least one selected from the group consisting of: irritable bowel syndrome (MS), ulcerative colitis, acid reflux, Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic, Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronic constipation, Chronic diarrhea, and Pancreatitis. In one embodiment, the cardiac-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation, Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiac surgery derived cough, heart block, Atrial Contractions, Tachycardia, and Congestive Heart Failure. In one embodiment, the pulmonary-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and Bronchospasm. In one embodiment, the metabolic-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, and hypercholesteremia.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.

As will be apparent to one of ordinary skill in the art from a reading of this disclosure, the embodiments of the present disclosure can be embodied in forms other than those specifically disclosed above. The particular embodiments described herein are, therefore, to be considered as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the invention is as set forth in the appended claims and equivalents thereof, rather than being limited to the examples contained in the foregoing description.

All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited herein are not admitted to be prior art.

EXAMPLES

Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.

Example 1: Treatment of Post-Tonsillectomy Pharyngeal or Oropharyngeal Pain

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from post-tonsillectomy pharyngeal, or oropharyngeal pain.

500 patients that had previously undergone a tonsillectomy were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear three times per day, for a duration of ten days after the tonsillectomy.

Results

Out of the 500 patients treated, 495 patients reported significant reduction in pharyngeal and/or oropharyngeal pain.

Example 2: Treatment of Post Adenoidectomy Pharyngeal or Oropharyngeal Pain

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from post-adenoidectomy pharyngeal, or oropharyngeal pain.

200 patients that had previously undergone an adenoidectomy were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear two times per day, for a duration of seven days after the adenoidectomy.

Results

Out of the 200 patients treated, 200 patients reported significant reduction in pharyngeal and/or oropharyngeal pain.

Example 3: Treatment of Asthma

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from chronic asthma and acute asthmatic attack.

10 patients with asthma were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear in the morning, for two months.

A patient suffering from a severe acute asthma attack was also treated by immediately filling the patient's ear canal with the aforementioned pharmaceutical composition.

Results

Out of the 10 patients treated, 10 patients reported significant reduction in asthmatic attacks.

Further, the patient suffering from the severe asthma attack experienced a dramatic increase in the amount of oxygen reaching his lungs within 60 minutes of the treatment.

Example 4: Treatment of Obesity (i.e. a Method of Appetite Suppression)

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from obesity.

5 overweight patients were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear in the morning, for an indefinite period of time.

Results

Out of the 5 patients treated, all 5 patients reported significant reduction in appetite while utilizing the treatment. The significant reduction in appetite led to weight loss.

Example 5: Treatment of Neurogenic Cough

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from neurogenic cough.

4 patients suffering from neurogenic cough were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear two times per day, for a duration of seven days and then only as needed.

Results

Out of the 4 patients treated, all 4 patients reported significant reduction in cough.

Example 6: Treatment of Globus Hystericus

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from globus hystericus.

2 patients suffering from globus hystericus were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear one time per day, for an indefinite period of time as needed.

Results

Out of the 2 patients treated, all 2 patients reported significant reduction in throat tightness.

Example 7: Treatment of Spasmodic Dysphonia

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from spasmodic dysphonia.

One (1) patient suffering from spasmodic dysphonia was instructed to utilize six drops of a pharmaceutical composition comprising (≈54.0 antipyrine mg) and benzocaine (≈14.0 mg), in each ear one time per day, for an indefinite period of time as needed.

Results

The patient reported significant reduction in throat hoarseness and vocal cord spasms almost immediately upon using the treatment.

Example 8: Treatment of Laryngeal Pain

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from laryngeal pain.

2 patients suffering from laryngeal pain were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear one time per day, for an indefinite period of time as needed.

Results

Out of the 2 patients treated, all patients reported significant reduction in laryngeal pain.

Example 9: Treatment of Gastroesophageal Reflux Disease

Protocol

A test of a preferred embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from Gastroesophageal Reflux Disease (GERD).

2 patients suffering from GERD were instructed to utilize six drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each ear one time per day, for an indefinite period of time as needed.

Results

Out of the 2 patients treated, all 2 patients reported significant reduction in acid reflux and heartburn.

The results from the aforementioned clinical experiments can be found below in Table 1.

TABLE 1 Clinical Experiments Number of Treatment Subjects % of Subjects Protocol Exhibiting Exhibiting Number of (1 mL ≈ Amount Clinical Clinical Subjects 15-20 of Time Improvement Improvement Disease Treated Treated drops) Treated in Symptoms in Symptoms Post- 500 6 drops per For 10 495  99% Tonsillectomy ear 3 times days post Pharyngeal or per day operation Oropharyngeal Pain Post- 200 6 drops per For 7 200 100% Adenoidectomy ear 2 times days post Pharyngeal or per day operation Oropharyngeal Pain Asthma 10 6 drops per For 2 10 100% ear in the months morning Obesity via 5 6 drops per Daily 5 100% Appetite ear in the Suppression morning Neurogenic 4 6 drops per 7 days 4 100% Cough ear 2 times and then per day as needed Globus 2 6 drops per As 2 100% Hystericus ear once a needed day Spasmodic 1 6 drops per As 1 100% Dysphonia ear once a needed day Laryngeal Pain 2 6 drops per As 2 100% ear once a needed day Gastroesophageal 2 6 drops per As 2 100% Reflux Disease ear once a needed (GERD) day

Example 10: Treatment of Diseases

Protocol

A test of an embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from a disease associated with a particular cranial nerve, wherein the disease is a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a Gastroenterology/Urology (GU)-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction.

Patients suffering from a neurology-psychiatry-related affliction, an ear-nose-throat (ENT)-related affliction, a GU-related affliction, a gastrointestinal (GI)-related affliction, a cardiac-related affliction, a pulmonary-related affliction, or a metabolic-related affliction were instructed to utilize drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg) (treatment protocol, “AB” Tmt Protocol) or drops of a pharmaceutical composition comprising lidocaine (≈40.0 mg) and tetracaine (≈5.0 mg) (treatment protocol, “LAT” Tmt Protocol), in one or both ears, at least one time per day (for example, either in the morning or at night), for a period of time as needed (Tmt Time). The LAT otic solution used in the tests comprises 4% Lidocaine, 0.5% Tetracaine, 1/100,000 Epinephrine, and Anhydrous Glycerine. The AB otic solution used in the tests comprises 5.4% Antipyrine, 1.4% Benzocaine, Oxyquinoline Sulfate, and Anhydrous Glycerine.

TABLE 2 Clinical Experiments with Neurology-psychiatry-related afflictions Tmt # of Subjects Neurology- Protocol Exhibiting psychiatry- # of (1 mL ≈ Clinical related Subjects 15-20 Tmt Improvement Improvement in affliction Treated drops) Time in Symptoms Symptoms reported Chronic 5 LAT: 6 as 4 More energy Fatigue drops per needed More activity Syndrome ear 1×/day Less fatigue 3 AB: 6 4 wks 2 Less muscle and joint drops per pain ear 1×/day 70% reduction in symptoms --w/both tmts Fibromyalgia 5 LAT: 6 4 wks 4 Less muscle and joint (chronic) drops per pain ear 1×/day 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Epilepsy 1 LAT: 6 4 wks 1 less seizures by 90% (Absence drops per Seizures) ear 1×/day 2 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Obsessive 3 LAT: 6 4 wks 3 less repetitive behavior Compulsive drops per less vomiting in Disorder ear 1×/day bulimics Panic Attacks 4 LAT: 6 4 wks 2 75% less panic attacks drops per ear 1×/day 4 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Post-Traumatic 1 LAT: 6 4 wks 1 Better sleep Stress Disorder drops per Less anxiety ear 1×/day Less nightmares Decrease in startle reflex by >50% 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Tourette’s 1 LAT: 6 4 wks 1 decreased tic activity Syndrome drops per and movement ear 1×/day Focal Dystonia 1 LAT: 6 4 wks 1 50% less eye blinking drops per ear 1×/day 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Anxiety 5 LAT: 6 4 wks 4 70% reduction in drops per nervousness ear 1×/day less need for anxiolytics 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Depression 5 LAT: 6 4 wks 4 Less depression drops per Less fatigue ear 1×/day 70% increase in activity 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Restless Leg 5 LAT: 6 4 wks 4 ≥70% reduction in leg Syndrome drops per movements ear 1×/day 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Dysautonomia 5 LAT: 6 4 wks 4 ≥70% reduction in drops per parasympathetic and ear 1×/day sympathetic symptoms 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Familial 5 LAT: 6 4 wks 5 ≥70% reduction in hand Tremor drops per shaking/tremor ear 1×/day 2 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Migraine pain 5 LAT: 6 4 wks 4 ≥70% reduction in drops per migraine headaches per ear 1×/day month (frequency, duration, and intensity) 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Autism 5 LAT: 6 4 wks 5 Less outbursts spectrum drops per Calmer disorder ear 1×/day Better speech More focused 3 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Anxiety 5 LAT: 6 4 wks 5 ≥75% reduction in Headaches drops per headaches per month ear 1×/day (frequency, duration, and intensity) 5 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Sleeplessness 5 LAT: 6 4 wks 4 better and continuous drops per sleep ear 1×/day Multiple 1 LAT: 6 4 wks 1 ≥50% reduction in Sclerosis drops per muscle pain ear 1×/day more muscle strength 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Peripheral 5 LAT: 6 4 wks 4 ≥50% reduction in Neuropathy drops per peripheral pain ear 1×/day 5 AB: 6 4 wks 4 --w/both tmts drops per ear 1x/day Apraxia 2 LAT: 6 4 wks 2 50% better speech as drops per noted by parents (better ear 1×/day word pronunciation) 2 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Neck and 5 LAT: 6 4 wks 5 ≥50% reduction in pain Shoulder Pain drops per ear 1×/day 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Parkinson’s 2 LAT: 6 4 wks 2 Less tremors and pain Disease drops per Better Balance ear 1×/day 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day General 4 LAT: 6 4 wks 3 less neck, back, arm, Somatic drops per leg, shoulder, and chest Afferent Pain- ear 1×/day pain Neuromuscular 2 AB: 6 4 wks 1 --w/both tmts Pain drops per ear 1×/day General 4 LAT: 6 4 wks 3 ≥50% reduction in pain Somatic drops per requiring less pain Afferent Pain- ear 1×/day medications Joint Pain 3 AB: 6 4 wks 2 --w/both tmts (nonspecific) drops per ear 1×/day General 4 LAT: 6 4 wks 3 reduction in pain Somatic drops per Afferent Pain- ear 1×/day Sciatica pain General 4 LAT: 6 4 wks 3 reduction in pain Somatic drops per Afferent Pain- ear 1×/day Arthritis pain General 4 LAT: 6 4 wks 3 reduction in pain Somatic drops per Afferent Pain- ear 1×/day Shingles Pain General 3 LAT: 6 4 wks 3 ≥70% reduction in Somatic drops per peripheral pain signals Afferent Pain- ear 1×/day less electrical, sharp Reflex pain Sympathetic 1 AB: 6 4 wks 1 --w/both tmts Dystrophy pain drops per ear 1×/day General 5 LAT: 6 4 wks 4 ≥70% reduction in Visceral drops per esophageal, stomach, Afferent Pain ear 1×/day intestinal, bladder, and pelvic pain 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Opiate 5 LAT: 6 4 wks 3 Reduction of Muscle Withdrawal drops per aches, back pains, ear 1×/day Nausea, Vomiting, sweating, diarrhea 5 AB: 6 4 wks 3 --w/both tmts drops per ear 1×/day Dysarthria 5 LAT: 6 4 wks 3 50% better intelligible drops per speech ear 1×/day 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Attention 5 LAT: 6 4 wks 4 Calmer Deficit drops per More focused Hyperactivity ear 1×/day Less frequent long- Disorder lasting emotional (ADHD) outbursts 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Nonspecific 4 LAT: 6 4 wks 4 50% less tremors hand tremors drops per ear 1×/day 2 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Stuttering 2 LAT: 6 4 wks 2 50% less stuttering drops per ear 1×/day 2 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Cerebral Palsy 1 LAT: 6 4 wks 1 Neuromuscular drops per modulation enhanced ear 1×/day better balance walks straighter speech more intelligible 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Raynaud’s 2 LAT: 6 4 wks 2 Better circulation Phenomenon drops per 50% less discoloration ear 1×/day 50% less cyanosis Better warmth to hand 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Excessive 3 LAT: 6 4 wks 2 ≥70% reduction in Sweating drops per perspiration ear 1×/day 2 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day

TABLE 3 Clinical Experiments with ear-nose-throat (ENT)-related afflictions. Tmt # of Subjects Protocol Exhibiting % of Subjects # of (1 mL ≈ Clinical Exhibiting Clinical ENT-related Subjects 15-20 Tmt Improvement Improvement in affliction Treated drops) Time in Symptoms Symptoms Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Pain drops per pain ear 1×/day Reduction of pain medications 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day Pharyngeal Pain 50 LAT: 6 4 wks 50 ≥70% reduction in drops per throat pain ear 1×/day 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day Laryngeal Pain  5 LAT: 6 4 wks  5 ≥50% reduction in drops per laryngeal pain ear 1×/day  5 AB: 6 4 wks  5 --w/both tmts drops per ear 1×/day Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Pain drops per pain ear 1×/day Reduction of pain medications 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day Neurogenic Cough  5 LAT: 6 4 wks  5 ≥70% reduction in drops per cough ear 1×/day  5 AB: 6 4 wks  5 --w/both tmts drops per ear 1×/day Globus Hystericus  5 LAT: 6 4 wks  5 ≥70% reduction in drops per tightness of throat ear 1×/day fullness  2 AB: 6 4 wks  2 --w/both tmts drops per ear 1×/day Spasmodic  5 LAT: 6 4 wks  4 ≥70% reduction in Dysphonia drops per dysphonia ear 1×/day  1 AB: 6 4 wks  1 --w/both tmts drops per ear 1×/day Snoring  5 LAT: 6 4 wks  4 ≥50% reduction in drops per snoring ear 1×/day  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Allergic Rhinitis  5 LAT: 6 4 wks  4 ≥50% reduction in drops per sneezing, sniffling, ear 1×/day and congestion Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Pain drops per pain ear 1×/day Reduction of pain medications 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Chronic Sinusitis  5 LAT: 6 4 wks  4 ≥50% reduction in drops per mucous discharge, ear 1×/day sneezing, and congestion  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Chronic Nasal  5 LAT: 6 4 wks  4 ≥50% reduction in Congestion drops per airway obstruction ear 1×/day  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Allergic  5 LAT: 6 4 wks  5 ≥50% reduction in Conjunctivitis drops per burning, redness, and ear 1×/day tearing  5 AB: 6 4 wks  5 --w/both tmts drops per ear 1×/day Sneezing  5 LAT: 6 4 wks  5 ≥70% reduction in drops per sneezing ear 1×/day  5 AB: 6 4 wks  5 --w/both tmts drops per ear 1×/day Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Pain drops per pain ear 1×/day Reduction of pain medications 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day Hiccups (acute and  5 LAT: 6 4 wks  4 ≥70% reduction in chronic) drops per hiccups ear 1×/day  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Rhinitis  5 LAT: 6 4 wks  4 reduction of drops per congestion, runny ear 1×/day nose, and sneezing  5 AB: 6 4 wks  4 --w/both tmts drops per ear 1×/day Tinnitus  5 LAT: 6 4 wks  1 Noticeable 50% drops per reduction in ringing ear 1×/day in ear Dysphagia  5 LAT: 6 4 wks  4 50% easier to drops per swallow ear 1×/day  3 AB: 6 4 wks  2 --w/both tmts drops per ear 1×/day Ear Pain (acute and  5 LAT: 6 4 wks  2 70% less ear pain chronic) drops per ear 1×/day  8 AB: 6 4 wks  5 --w/both tmts drops per Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Pain drops per pain ear 1×/day Reduction of pain medications 50 AB: 6 4 wks 50 --w/both tmts drops per ear 1×/day ear 1×/day Neck Pain  3 LAT: 6 4 wks  2 50% less neck pain drops per ear 1×/day  3 AB: 6 4 wks  2 --w/both tmts drops per ear 1×/day Dry Eye Syndrome  4 LAT: 6 4 wks  3 less redness, matting, drops per and dry eyes ear 1×/day  2 AB: 6 4 wks  1 --w/both tmts drops per ear 1×/day Trigeminal  5 LAT: 6 4 wks  4 50% less facial pain Neuralgia Pain drops per ear 1×/day  3 AB: 6 4 wks  2 --w/both tmts drops per ear 1×/day Temporomandibular  5 LAT: 6 4 wks  4 ≥70% reduction of Joint Pain drops per jaw pain ear 1×/day  3 AB: 6 4 wks  2 --w/both tmts drops per ear 1×/day

TABLE 4 Clinical Experiments with Gastroenterology/Urology (GU)-related afflictions Tmt # of Subjects Protocol Exhibiting % of Subjects # of (1 mL ≈ Clinical Exhibiting Clinical GU-related Subjects 15-20 Tmt Improvement Improvement in affliction Treated drops) Time in Symptoms Symptoms Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops per urination frequency ear 1×/day and urgency, and nocturia decreased bladder spasm 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Interstitial Cystitis 2 LAT: 6 4 wks 2 ≥50% reduction of drops per burning, dysuria, and ear 1×/day pressure 1 AB: 6 4 wks 1 ≥90% reduction in drops per pain during urination ear 1×/day --w/both tmts Dysmenorrhea 5 LAT: 6 4 wks 5 ≥50% reduction of drops per menorrhea pain ear 1×/day 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Pelvic Pain 5 LAT: 6 4 wks 5 ≥50% reduction of drops per pelvic pain from ear 1×/day infection, surgery or ovaries, and fibroids 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Chronic Prostatitis 1 LAT: 6 4 wks 1 ≥50% reduction in Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops per urination frequency ear 1×/day and urgency, and nocturia decreased bladder spasm 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Pain 1 drops per 4 wks 1 pain and pressure ear 1×/day AB: 6 --w/both tmts drops per ear 1×/day eclampsia LAT: 6 4 wks expect to see drops per Reduction of rapid ear 1×/day weight gain from body fluids, abdominal pain, hpt, and urine output, nausea and vomiting, blurred vision AB: 6 4 wks --w/both tmts drops per ear 1×/day Preeclampsia LAT: 6 4 wks expect to see drops per Reduction of HPT, ear 1×/day headaches, Nausea and Vomiting AB: 6 4 wks --w/both tmts drops per ear 1×/day HELLP Syndrome LAT: 6 4 wks expect to see drops per Reduction of HPT, ear 1×/day abdominal pain, headaches, nausea and vomiting, shoulder pain, and swelling AB: 6 4 wks --w/both tmts drops per ear 1×/day Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops per urination frequency ear 1×/day and urgency, and nocturia decreased bladder spasm 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Cystitis Pain 5 LAT: 6 4 wks 5 ≥50% reduction in drops per pain ear 1×/day 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Kidney Pain (from 2 LAT: 6 4 wks 2 ≥50% reduction in stone, infection, drops per pain from stone, tumor) ear 1×/day infection, tumor, etc 1 AB: 6 4 wks 1 --w/both tmts drops per ear 1×/day Enuresis 5 LAT: 6 4 wks 5 ≥50% reduction in bed drops per wetting ear 1×/day 3 AB: 6 4 wks 3 --w/both tmts drops per ear 1×/day Dysuria 5 LAT: 6 4 wks 5 ≥50% reduction in drops per pain with urination ear 1×/day (e.g., bladder infection) 2 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops per urination frequency ear 1×/day and urgency, and nocturia decreased bladder spasm 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Dyspareunia 5 LAT: 6 4 wks 4 ≥70% reduction in drops per painful intercourse ear 1×/day 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Encopresis 1 LAT: 6 4 wks 1 ≥75% reduction in drops per episodes of defecation ear 1×/day in clothing in children older than 3 2 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Menorrhagia 5 LAT: 6 4 wks 5 ≥75% reduction in (Heavy Flow drops per flow and all had Periods) ear 1×/day decreased number of days (i.e. 2 days) 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Frequent 5 LAT: 6 4 wks 5 ≥50% reduction in Urination drops per frequency ear 1×/day (daily and nightly) 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops per urination frequency ear 1×/day and urgency, and nocturia decreased bladder spasm 3 AB: 6 4 wks 2 --w/both tmts drops per ear 1×/day Menometrorrhagia 4 LAT: 6 4 wks 4 ≥50% reduction in (Prolonged drops per bleeding from cycle Vaginal Bleeding) ear 1×/day period reduced by at least 2 days 2 AB: 6 4 wks 2 --w/both treatments drops per ear 1×/day

TABLE 5 Clinical Experiments with Gastrointestinal (GI)-related afflictions Tmt # of Subjects % of Subjects Protocol Exhibiting Exhibiting GI- # of (1 mL ≈ Clinical Clinical related Subjects 15-20 Tmt Improvement Improvement affliction Treated drops) Time in Symptoms in Symptoms Irritable 5 LAT: 6 4 wks 5 ≥50% reduction Bowel drops per in diarrhea and Syndrome ear 1×/day constipation 3 AB: 6 4 wks 2 --w/ both drops per treatments ear 1×/day Ulcerative 2 LAT: 6 4 wks 2 ≥50% reduction Colitis drops per in pain, ear 1×/day diarrhea, 1 AB: 6 4 wks 1 cramping, rectal bleeding, and joint pain Irritable 5 LAT: 6 4 wks 5 ≥50% reduction Bowel drops per in diarrhea and Syndrome ear 1×/day constipation 3 AB: 6 4 wks 2 --w/ both drops per treatments ear 1×/day --w/ both drops per treatments ear 1×/day Gastro- 5 LAT: 6 4 wks 5 ≥50% reduction esophageal drops per in bloating, gas, Reflux ear 1×/day heartburn, (Acid 5 AB: 6 4 wks 2 and pain Reflux) drops per --w/ both ear 1×/day treatments Gastritis 5 LAT: 6 4 wks 5 ≥50% reduction Pain drops per in stomach ear 1×/day pain and 3 AB: 6 4 wks 2 burning drops per --w/ both ear 1×/day treatments Gastro- 1 LAT: 6 4 wks 1 ≥50% reduction enteritis drops per in nausea, ear 1×/day vomiting, diarrhea, abdominal cramping 1 AB: 6 4 wks 1 ≥75% reduction drops per in nausea ear 1×/day and vomiting, abdominal cramping, diarrhea Hyper- 1 LAT: 6 4 wks 1 25% reduction emesis drops per in nausea Gravi- ear 1×/day and vomiting darum Pediatric 1 LAT: 6 4 wks 1 ≥50% reduction Colic drops per in cramp pain ear 1×/day and bowel 1 AB: 6 4 wks 1 movements drops per -- w/ both treatments Irritable 5 LAT: 6 4 wks 5 ≥50% reduction Bowel drops per in diarrhea and Syndrome ear 1×/day constipation 3 AB: 6 4 wks 2 --w/ both drops per treatments ear 1×/day ear 1×/day Appetite 5 LAT: 6 4 wks 4 at least 4 Sup- drops per lb. weight pression ear 1×/day loss per month 3 AB: 6 4 wks 2 less snacking drops per decreased meal ear 1×/day size intake --w/ both treatments Gall 2 LAT: 6 4 wks 2 ≥50% reduction Bladder drops per in pain Pain ear 1×/day -- w/ both 2 AB: 6 4 wks 2 treatments drops per ear 1×/day Chronic 5 LAT: 6 4 wks 4 At least 50% consti- drops per more bowel pation ear 1×/day movements 3 AB: 6 4 wks 2 per week drops per -- w/ both ear 1×/day treatments Chronic 5 LAT: 6 4 wks 4 At least 50% diarrhea drops per less episodes ear 1×/day of diarrhea 3 AB: 6 4 wks 2 -- w/ both drops per treatments ear 1×/day Pancreatitis 4 LAT: 6 4 wks 3 ≥50% reduction pain drops per in abdominal ear 1×/day pain -- w/ both treatments Irritable 5 LAT: 6 4 wks 5 ≥50% reduction Bowel drops per in diarrhea and Syndrome ear 1×/day constipation 3 AB: 6 4 wks 2 --w/ both drops per treatments ear 1×/day 2 AB: 6 4 wks 1 drops per ear 1×/day

TABLE 6 Clinical Experiments with Cardiac-related afflictions Tmt # of Subjects % of Subjects Protocol Exhibiting Exhibiting Cardiac- # of (1 mL ≈ Clinical Clinical related Subjects 15-20 Tmt Improvement Improvement affliction Treated drops) Time in Symptoms in Symptoms Paroxysmal, 1 LAT: 6 4 wks 1 50% less atrial lone, vagal drops per fibrillation mediated ear 1×/day atrial fibrillation Orthostatic 2 LAT: 6 4 wks 2 70% less (Neurogenic) drops per episodes of Hypotension ear 1×/day drops of 1 AB: 6 4 wks 1 blood pressure drops -- w/ both per ear treatments 1×/day Reflex 1 LAT: 6 4 wks 1 decreased Asystolic drops per seizures and Syncope ear 1×/day spasms Postural 2 LAT: 6 4 wks 2 No drop in Orthostatic drops per blood pressure Tachycardia ear 1×/day No increase in Syndrome heart rate Paroxysmal, 1 LAT: 6 4 wks 1 50% less lone, vagal drops per atrial mediated ear 1×/day fibrillation atrial fibrillation (POTS) 2 AB: 6 4 wks 2 -- w/ both drops treatments per ear 1×/day Vasovagal 5 LAT: 6 4 wks 5 100% Reflex drops per reduction in ear 1×/day vasovagal 5 AB: 6 4 wks 5 reflex drops syncope per ear -- w/ both 1×/day treatments Cough from 1 LAT: 6 4 wks 1 decreased cardiac drops per coughing surgery ear 1×/day incidents Premature 3 LAT: 6 4 wks 3 normalization Atrial drops per of heartbeats Contractions ear 1×/day Supra- 3 LAT: 6 4 wks 3 Decreased ventricular drops per palpitations, Tachycardia ear 1×/day chest discomfort, and light- headedness

TABLE 8 Clinical Experiments with Pulmonary-related afflictions Tmt # of Subjects % of Subjects Protocol Exhibiting Exhibiting Pulmonary- # of (1 mL ≈ Clinical Clinical related Subjects 15-20 Tmt Improvement Improvement affliction Treated drops) Time in Symptoms in Symptoms Asthma 100 LAT: 6 4 wks 100 Reduced cough drops per Reduce inhaler ear 1×/day usage 100 AB: 6 4 wks 100 -- w/ both drops per treatments ear 1×/day COPD 2 LAT: 6 4 wks 2 Reduced cough drops per Reduced chest ear 1×/day pressure 2 AB: 6 4 wks 2 Decreased drops per shortness of ear 1×/day breath -- w/ both treatments Congestive LAT: 6 4 wks Expect to see Heart drops per a decrease in Failure ear 1×/day coughing and (CHF) AB: 6 4 wks wheezing; drops per decreased ear 1×/day water retention; and decreased dizziness and fatigue Chronic 5 LAT: 6 4 wks 5 Decreased Bronchitis drops per coughing and symptoms ear 1×/day reduction of 5 AB: 6 4 wks 5 mucous drops per Less chest ear 1×/day tightness -- w/ both treatments Asthmatic 5 LAT: 6 4 wks 5 Decreased Bronchitis drops per coughing and symptoms ear 1×/day reduction of 1 AB: 6 4 wks 1 mucous drops per -- w/ both ear 1×/day treatments Cystic 1 LAT: 6 4 wks 1 Better Fibrosis drops per breathing ear 1×/day capability

TABLE 7 Clinical Experiments with Metabolism-related afflictions Tmt # of Subjects % of Subjects Protocol Exhibiting Exhibiting Metabolism- # of (1 mL ≈ Clinical Clinical related Subjects 15-20 Tmt Improvement Improvement affliction Treated drops) Time in Symptoms in Symptoms Hypertension 5 LAT: 6 4 wks 4 20% drops per reduction in ear 1×/ systolic day pressure 5 AB: 6 4 wks 4 10% drops per reduction in ear 1×/ diastolic day pressure -- w/ both treatments Diabetes 5 LAT: 6 4 wks 4 20% reduction drops per in a.m. ear 1×/ fasting, less day hunger 5 AB: 6 4 wks 4 -- w/ both drops per treatments ear 1×/ day Hyper- 5 LAT: 6 4 wks 4 reduction glycemia drops per in serum ear 1×/ glucose day levels to desired target Hyper- 5 LAT: 6 4 wks 3 reduction in cholesteremia drops per serum ear 1×/ cholesterol day levels to desired target

The diseases that are treatable by the disclosed methodology are numerous. Any disease that is associated with an organ or bodily tissue that is innervated by the particular nerve could potentially be treated by the present methods. Particular mention of the following diseases treatable by the present methods is made: asthma, neurogenic cough, globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease, and obesity. The present methods are also suitable for treating post-tonsillectomy or post-adenoidectomy pharyngeal pain, or oropharyngeal pain.

In yet other embodiments, the diseases treatable by the disclosed methodology include, but are not limited to: cardiac diseases, paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope, postural orthostatic tachycardia syndrome (POTS), excessive gag reflex, esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain, esophageal neuralgia, gastritis, dyspepsia, gall bladder disease, colecistitis pain, abdominal pain, esophageal motility disorder or esophageal dysmotility, spastic colon, pancreatic pain or spasms, pediatric colic, rectal spasms and pain, bladder spasm (overactive bladder), interstitial cystitis, dysmenorrhea, premature labor, pelvic pain, chronic pelvic pain, chronic prostatitis pain, eclampsia, preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome, Cohn's disease, ulcerative colitis, reflux disease, gastritis, gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic, hepato-renal syndrome, appetite suppression, gall bladder pain, inflammation of the esophagus, inflammation of the stomach, inflammation of the colon, kidney pain (from stone, infection, or tumor), enuresis, dysuria, dyspareunia, encopresis, heavy flow periods, frequent urination, prolonged vaginal bleeding, inhibit erections, prevention of premature ejaculation, inhibit excessive sweating, ureteral spasms, menstrual cramps, uterine spasms, ovarian pain and spasms, fallopian tube pain and spasms, pediatric asthma, adult asthma, chronic obstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis, asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis, inflammation of the lung, emphysema, pleuritic chest pain, intercostal muscle pain, nerve pain, bronchospasm secondary to intubation and extubation, angina pectoris, cardiac vagal blockage, vasovagal reflex blockage, bradycardia, hypotension, orthostatic hypotension, hypertension, diabetes, shock, septic shock, reduction of blood sugar, inflammation of the pancreas, syncope secondary to vagal or cardiac reasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin, neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chronic laryngitis, post extubation and intubation laryngospasms, palatal myoclonus, post-tonsillectomy pain, snoring, allergic rhinitis, vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome, fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panic attacks, post-traumatic stress disorder, Tourette's syndrome, focal dystonia, tic doloreaux, bulimia, anxiety, depression, restless leg syndrome, dysautonomia, familial intentional tremor, migraines, autism spectrum, anxiety headaches, insomnia, multiple sclerosis, modulation of the reticular activating system, peripheral neuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

In particular, improvement was reported in over half of the patients treated in accordance with the above methods, where there were minimum of 5 patients treated for symptoms or conditions associated with the following diseases or disorders, vasovagal reflex blockage, chronic bronchitis, asthmatic bronchitis, hypotension, hypertension, diabetes, bladder spasm, dysmenorrhea, pelvic pain, cystitis pain, enuresis, dysuria, dyspareunia, heavy menstrual flow periods, frequent urination, spasmodic dysphonia, snoring, allergic rhinitis, vasomotor rhinitis, chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, dysphagia, irritable bowel syndrome, gastritis, appetite suppression, chronic fatigue syndrome, fibromyalgia, anxiety, depression, restless leg syndrome, familial intentional tremor, migraines, autism spectrum, anxiety headaches, insomnia, sleep disorders, apraxia, and neck and shoulder pain. Similar positive results (i.e., positive results reported for all or more than half of all patients treated) also were seen with the other listed diseases or closely-related diseases.

While the methods for treating various diseases associated with the vagus and other cranial nerves have been described in the application in connection with various embodiments, the scope of the methods is not intended to be limited to the particular embodiments so disclosed. But on the contrary, the methods are intended to cover such alternatives, modifications, and equivalents, as may be included within the scope and spirit of the below claims.

Example 11—Treatment of Diseases

Embodiments of the invention comprise modulation of the general somatic afferent nerves and general visceral afferent nerves, by administering one or more anesthetic(s), (for example, either alone or in combination, such as Lidocaine or Bupivicaine) in solution with a carrier, such as an excipient, Polyetheylene Glycol. “Modulation” can refer to the ability of the compounds and/or compositions described herein to either enhance (i.e., stimulate) or inhibit (i.e., block) the activity of nerves, such as one or more of cranial nerves, general somatic afferent fibers, general visceral afferent fibers, and the like. For example, the general visceral afferent fibers (GVA) conduct sensory impulses (usually pain or reflex sensations) from the internal organs, glands, and blood vessels to the central nervous system. They are considered to be part of the autonomic nervous system. Embodiments described herein can modulate the general visceral afferent fibers, such as those of the vagus nerve.

The invention further provides for the modulation of the sympathetic and parasympathetic nervous systems, by auricular anesthesia to auricular branches of the vagus, glossopharyngeal, and facial nerves and their connections to the sympathetic ganglion. Anesthesia to the ganglion of cranial nerves 5, 7, 9 and 10, and the sympathetic nervous system results in their respective downward modulation. Overactive sympathetic and parasympathetic nervous systems are clearly implicated in the development and metastasis of certain types of malignancies, namely Prostate Cancer, Ovarian Cancer, Breast Cancer, and Lymphoblastic Leukemia.

Embodiments of the invention comprise treating, preventing, or providing symptomatic relief of infection-related afflictions. The term “infection-related affliction” can refer to an affliction that comprises or results from the invasion of a subject's body and/or body tissue by microorganisms, their multiplication, and the reaction of the subject's immune system to the microorganism. Non-limiting examples of infections as described herein comprise those of the Herpes Simplex virus (HSV type 1 or HSV type 2, for example) and the Varicella-zoster virus (VZV).

Embodiments of the invention comprise treating, preventing, or providing symptomatic relief of skin-related afflictions. The term “skin-related affliction” can refer to an affliction that comprises or affects the integumentary system which covers the entire surface of the body and is composed of skin, hair, nails, and related muscles and glands. Skin-related afflictions can be temporary or permanent. Non-limiting examples of skin conditions comprise facial flushing (such as Hot Flashes), facial blushing, Alopecia Areata, Atopic Dematitis, Chronic Eczema, Acne Vulgaris, Oily Skin, Rosacea, or Morgellons Disease.

Embodiments of the invention comprise treating, preventing, or providing symptomatic relief of cell proliferation-related afflictions. The term “cell proliferation-related affliction” can refer to an affliction that comprises or results from the uncontrollable proliferation of cells within a subject's tissues and the reaction of the subject's immune system to the cell proliferation and/or growth. Non-limiting examples of cell-proliferation related conditions comprise cancers (e.g., solid tumors and liquid cancers) and mastocytosis.

Embodiments of the invention comprise treating, preventing, or providing symptomatic relief of blood flow-related afflictions. The term “blood flow-related affliction” can refer to an affliction that is characterized by alterations in the flow of blood through a subject's vascular system and/or alters the flow of blood through a subject's vascular system. For example, a blood flow-related affliction can result in an increase in the flow of blood through a subject's vascular system. As another example, a blood flow-related affliction can result in a decrease in the flow of blood through a subject's vascular system. Non-limiting examples of blood flow-related afflictions comprise erectile dysfunction, sickle cell disease, or wound healing.

A test of an embodiment of the present method was conducted to evaluate the efficacy of the method for treating patients suffering from an infection-related affliction, cardiac-related afflictions, metabolism-related afflictions, gastroenterology/urology (GU)-related afflictions, skin-related afflictions, neurology-psychiatry-related, cell proliferation-related afflictions, and blood flow-related afflictions. Subjects suffering from such afflictions were instructed to utilize drops of a pharmaceutical composition comprising lidocaine (4%) and bupivacaine (2%), in one or both ears, at least one time per day (for example, either in the morning or at night), for a period of time as needed (Tmt Time).

TABLE 9 Clinical Experiments with Infection-related afflictions # of Subjects Exhibiting Infection- # of Tmt Clinical related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement Herpes 1 6 drops per at least 1 Prevent the Simplex 1 ear 1×/day 2 emergence of 1 4% weeks 1 herpes cold lidocaine; sores 1 2% 1 Shorten the Bupi- course of vacaine herpes cold sores Reduction in pain of herpes cold sores Herpes 6 drops per at least Prevent the Simplex 2 ear 1×/day 2 emergence of 4% weeks herpes cold lidocaine; sores 2% Shorten the Bupi- course of vacaine herpes cold sores Reduction in pain of herpes cold sores Varicella 1 6 drops per at least 1 Prevent the Zoster ear 1×/day 2 emergence of 1 4% weeks 1 Varicella lidocaine; infection 1 2% 1 Shorten the Bupi- course of vacaine Varicella infection Reduction in pain of Varicella infection

TABLE 10 Clinical Experiments with Cardiac-related afflictions # of Subjects Exhibiting Cardiac- # of Tmt Clinical related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement premature 10 6 drops per at least 9 Prevent the atrial ear 1×/day 2 development contraction 4% weeks of and atrial lidocaine; affliction tachycardia 2% Bupi- vacaine

TABLE 11 Clinical Experiments with Metabolism-related afflictions # of Subjects Exhibiting Metabolism- # of Tmt Clinical related Subjects Protocol Tmt Improvement Clinical affliction Treated (XYZ) Time in Symptoms Improvement Insulin 10 6 drops per at least 9 Resistance ear 1×/day 2 4% weeks lidocaine; 2% Bupi- vacaine

TABLE 12 Clinical Experiment with Gastroenterology/ Urology (GU)-related afflictions Gastro- # of Subjects enterology/ Exhibiting Urology # of Tmt Clinical (GU)-related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement Chronic 3 6 drops per at 3 Increased Renal ear 1×/day least 2 blood flow Failure 4% weeks lidocaine; 2% Bupi- vacaine

TABLE 13 Clinical Experiment with Skin-related afflictions # of Subjects Exhibiting Skin- # of Tmt Clinical Clinical related Subjects Protocol Tmt Improvement Improve- affliction Treated (XYZ) Time in Symptoms ment facial 9 6 drops per at 10 flushing ear 1×/day least (Hot 4% 2 weeks Flashes) lidocaine; 2% Bupi- vacaine facial 9 6 drops per at 10 blushing ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Alopecia 4 6 drops per at 4 Areata ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Atopic 2 6 drops per at 2 Dematitis ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Chronic 2 6 drops per at 2 Eczema ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Acne 3 6 drops per at 3 Vulgaris ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Oily Skin 3 6 drops per at 3 ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Rosacea 2 6 drops per at 2 ear 1×/day least 4% 2 weeks lidocaine; 2% Bupi- vacaine Mor- 6 drops per at gellons ear 1×/day least Disease 4% 2 weeks lidocaine; 2% Bupi- vacaine

TABLE 14 Clinical Experiment with Neuropology-Psychiatry-related affliction # of Subjects Neurology- Exhibiting Psychiatry- # of Tmt Clinical Clinical related Subjects Protocol Tmt Improvement Improve- affliction Treated (XYZ) Time in Symptoms ment Reflex 20 6 drops per at 20 Sympathetic ear 1×/day least Dystrophy 4% 2 lidocaine; weeks 2% Bupivacaine Sensory 1 6 drops per at 1 Processing ear 1×/day least Disorder 4% 2 lidocaine; weeks 2% Bupivacaine Decreased 2 6 drops per at 1 Libido ear 1×/day least 4% 2 lidocaine; weeks 2% Bupivacaine

TABLE 15 Clinical Experiment with Cell Proliferation-related afflictions # of Subjects Cell Pro- Exhibiting liferation- # of Tmt Clinical related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement Cancer 3 6 drops at 3 Modulation per ear least of the 1×/day 2 Sympathetic 4% weeks Nervous lidocaine; System 2% and the Bupi- prevention vacaine and spread of prostate cancer, lymphoblastic leukemia, ovarian cancer, breast cancer Prevention of side effects to chemotherapy (Side effects such as pain, fatigue, anxiety, and sympathetic nervous system over- stimulation) Masto- 1 6 drops per at 1 cytosis ear 1×/day least 4% 2 lidocaine; weeks 2% Bupi- vacaine

TABLE 16 Clinical Experiment with Blood Flow-related afflictions # of Subjects Blood Exhibiting Flow- # of Tmt Clinical related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement Erectile 1 6 drops per at least 1 Dysfunction ear 1×/day 2 weeks 4% lidocaine; 2% Bupi- vacaine Open 1 6 drops per at least 2 1 Increase in Wound ear 1×/day weeks peripheral Healing 4% blood flow lidocaine; 2% Bupi- vacaine Sickle 1 6 drops per at least 2 1 Cell ear 1×/day weeks Disease 4% lidocaine; 2% Bupi- vacaine

Example 12—Treatment of Pain

Embodiments of the invention further comprise treating pain, such as pain that results from a variety of diseases disclosed herein, by performing auricular anesthesia that indirectly anesthetizes paraspinal and paravertebral ganglion. Those respective ganglion receive general visceral afferent signals that are thus modulated. Those modulated signals travel from the paraspinal and paravertebral ganglion to the dorsal root ganglion, then to the dorsal grey horn of the spinal cord, where they meet with general somatic afferent signals. Modulated general visceral afferent signals modulate the general somatic afferent signals by this invention, thus modulates pain in both nervous system pathways.

Embodiments of the invention comprise methods of blocking pain from a variety of diseases that comprises performing auricular anesthesia of the ear canal and concha, resulting in anesthesia to branches of cervical nerves 2 and 3 (C2, C3) and cranial nerves 5, 7, 9, and 10. The tenth cranial nerve, or Vagus Nerve, has direct attachments to the eleventh (11) and twelfth (12) cranial nerves and the sympathetic ganglion.

As is known in the art, pain is typically treated by administering an anesthetic or analgesic directly to the site of the pain. For example, U.S. Pat. No. 6,093,417 (Petrus) teaches administration of a topical ear composition comprising a penetration enhancer directly to the ear itself for the purpose of reducing inflammation of the inner ear and providing pain relief of the inner ear. However, as described herein, the invention provided for a method for ameliorating pain in a subject comprising administering to the ear canal of a subject a pain relieving composition so as to ameliorate pain at a distal site (i.e, non-ear pain, away from the site of composition administration).

A test of an embodiment of the method described herein was conducted to evaluate the efficacy of the method for treating patients suffering from pain. Subjects suffering from pain were instructed to utilize drops of a pharmaceutical composition comprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg) (treatment protocol, “AB” Tmt Protocol) or drops of a pharmaceutical composition comprising lidocaine (≈40.0 mg) and tetracaine (≈5.0 mg) (treatment protocol, “LAT” Tmt Protocol), in one or both ears, at least one time per day (for example, either in the morning or at night), for a period of time as needed (Tmt Time). The LAT otic solution used in the tests comprises 4% Lidocaine, 0.5% Tetracaine, 1/100,000 Epinephrine, and Anhydrous Glycerine. The AB otic solution used in the tests comprises 5.4% Antipyrine, 1.4% Benzocaine, Oxyquinoline Sulfate, and Anhydrous Glycerine.

TABLE 17 Clinical Experiment with Pain-related afflictions # of Subjects Exhibiting # of Tmt Clinical Pain-related Subjects Protocol Tmt Improvement Clinical afflictions Treated (XYZ) Time in Symptoms Improvement Post- 500 6 drops For 10 495 Tonsillect- per ear days post omy 3 times operation Pharyngeal per day or Oropharyn- geal Pain Post-Adeno- 200 6 drops For 7 200 idectomy per ear days post Pharyngeal 2 times operation or per day Oropharyn- geal Pain Laryngeal 2 6 drops As 2 Pain per ear needed once a day Migraine 5 LAT: 6 4 wks 4 ≥70% Pain drops reduction in per ear migraine 1×/day headaches 3 AB: 6 4 wks 2 per month drops (frequency, per ear duration, and 1×/day intensity) --w/ both tmts Anxiety 5 LAT: 6 4 wks 5 ≥75% Headaches drops reduction in per ear headaches 1×/day per month 5 AB: 6 4 wks 2 (frequency, drops duration, per ear and intensity) 1×/day --w/ both tmts Peripheral 5 LAT: 6 4 wks 4 ≥50% Neuropathy drops reduction in per ear peripheral 1×/day pain 5 AB: 6 4 wks 4 --w/ both drops tmts per ear 1×/day Neck and 5 LAT: 6 4 wks 5 ≥50% Shoulder drops reduction Pain per ear in pain 1×/day --w/ both 3 AB: 6 4 wks 2 tmts drops per ear 1×/day General 4 LAT: 6 4 wks 3 less neck, Somatic drops back, arm, Afferent per ear leg, Pain- 1×/day shoulder, Neuro- 2 AB: 6 4 wks 1 and chest muscular drops pain Pain per ear --w/ both 1×/day tmts General 4 LAT: 6 4 wks 3 ≥50% Somatic drops reduction Afferent per ear in pain Pain-Joint 1×/day requiring Pain 3 AB: 6 4 wks 2 less pain (nonspecific) drops medications per ear --w/ both 1×/day tmts General 4 LAT: 6 4 wks 3 reduction Somatic drops in pain Afferent per ear Pain- 1×/day Sciatica pain General 4 LAT: 6 4 wks 3 reduction Somatic drops in pain Afferent per ear Pain- 1×/day Arthritis pain General 4 LAT: 6 4 wks 3 reduction Somatic drops in pain Afferent per ear Pain- 1×/day Shingles Pain General 3 LAT: 6 4 wks 3 ≥70% Somatic drops reduction in Afferent per ear peripheral Pain-Reflex 1×/day pain signals Sympathetic 1 AB: 6 4 wks 1 less Dystrophy drops electrical, pain per ear sharp pain 1×/day --w/ both tmts General 5 LAT: 6 4 wks 4 ≥70% Visceral drops reduction in Afferent per ear esophageal, Pain 1×/day stomach, 1 AB: 6 4 wks 1 intestinal, drops bladder, and per ear pelvic pain 1×/day --w/ both Post 50 LAT: 6 4 wks 50 tmts Tonsillect- drops ≥50% omy Pain per ear reduction 1×/day in pain 50 AB: 6 4 wks 50 Reduction drops of pain per ear medications 1×/day --w/ both tmts Pharyngeal 50 LAT: 6 4 wks 50 ≥70% Pain drops reduction in per ear throat pain 1×/day --w/ both 50 AB: 6 4 wks 50 tmts drops per ear 1×/day Laryngeal 5 LAT: 6 4 wks 5 ≥50% Pain drops reduction in per ear laryngeal 1×/day pain 5 AB: 6 4 wks 5 --w/ both drops tmts per ear 1×/day Ear Pain 5 LAT: 6 4 wks 2 70% less (acute and drops ear pain chronic) per ear --w/ both 1×/day tmts 8 AB: 6 4 wks 5 drops per ear 1×/day Neck Pain 3 LAT: 6 4 wks 2 50% less drops neck pain per ear --w/ both 1×/day tmts 3 AB: 6 4 wks 2 drops per ear 1×/day Trigeminal 5 LAT: 6 4 wks 4 50% less Neuralgia drops facial pain Pain per ear --w/ both 1×/day tmts 3 AB: 6 4 wks 2 drops per ear 1×/day Temporo- 5 LAT: 6 4 wks 4 ≥70% mandibular drops reduction Joint Pain per ear of jaw pain 1×/day --w/ both 3 AB: 6 4 wks 2 tmts drops per ear 1×/day Pelvic Pain 5 LAT: 6 4 wks 5 ≥50% drops reduction of per ear pelvic pain 1×/day from 3 AB: 6 4 wks 2 infection, drops surgery or per ear ovaries, and 1×/day fibroids --w/ both tmts Chronic 1 LAT: 6 4 wks 1 ≥50% Prostatitis drops reduction Pain per ear in pain 1×/day and pressure 1 AB: 6 4 wks 1 --w/ both drops tmts per ear 1×/day Cystitis 5 LAT: 6 4 wks 5 ≥50% Pain drops reduction per ear in pain 1×/day --w/ both 1 AB: 6 4 wks 1 tmts drops per ear 1×/day Kidney 2 LAT: 6 4 wks 2 ≥50% Pain (from drops reduction stone, per ear in pain from infection, 1×/day stone, tumor) 1 AB: 6 4 wks 1 infection, drops tumor, etc per ear --w/ both 1×/day tmts Gastritis 5 LAT: 6 4 wks 5 ≥50% Pain drops reduction in per ear stomach 1×/day pain and 3 AB: 6 4 wks 2 burning drops --w/ both per ear treatments 1×/day Gall 2 LAT: 6 4 wks 2 ≥50% Bladder drops reduction Pain per ear in pain 1×/day -- w/ both 2 AB: 6 4 wks 2 treatments drops per ear 1×/day Pancreatitis 4 LAT: 6 4 wks 3 ≥50% pain drops reduction in per ear abdominal 1×/day pain 2 AB: 6 4 wks 1 -- w/ both drops treatments per ear 1×/day

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention, and are covered by the following claims. 

What is claimed is:
 1. A method for ameliorating pain in a subject, the method comprising administering to an ear canal of a subject afflicted with a distal pain an effective amount of a pharmaceutical composition comprising at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.
 2. The method according to claim 1, wherein the anesthetic comprises benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine, ropivacaine, farmocaine, trimecaine, or a combination of the anesthetics listed herein.
 3. The method of claim 1, wherein the composition further comprises at least one analgesic comprising a pyrazolone derivative.
 4. The method of claim 3, wherein the pyrazolone derivative is selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone.
 5. The method of claim 1, wherein said pharmaceutical composition is administered in a concentration sufficient to physiologically alter the activity of the subject's particular cranial nerve compared to the physiological activity of that particular cranial nerve in a subject not administered the pharmaceutical composition.
 6. The method according to claim 5, wherein the particular cranial nerve is the trigeminal nerve, the facial nerve, the glossopharyngeal nerve, the accessory nerve, the hypoglossal nerve, the vagus nerve, or a combination thereof.
 7. The method according to claim 1, wherein the subject does not have an ear infection, ear pain, or a combination thereof.
 8. The method according to claim 1, wherein the pharmaceutical composition further comprises one or more of an antibiotic, a vasoconstrictor, glycerin, epinephrine, or acetic acid.
 9. The method according to claim 1, wherein the amount of anesthetic does not exceed 252 mg/day.
 10. The method of claim 3, wherein the amount of analgesic administered does not exceed 972 mg/day.
 11. The method of claim 1, wherein the pain comprises post-tonsillectomy pharyngeal or oropharyngeal pain, post-adenoidectomy pharyngeal or oropharyngeal pain, laryngeal pain, migraine pain, anxiety headaches, peripheral neuropathy, neck and shoulder pain, general somatic afferent pain, neuromuscular pain, joint pain, sciatica pain, arthritis pain, shingles pain, reflex sympathetic dystrophy pain, general visceral afferent pain, post tonsillectomy pain, pharyngeal pain, laryngeal pain, neck pain, trigeminal neuralgia pain, temporomandibular joint pain, pelvic pain, chronic prostatitis pain, cystitis pain, kidney pain, gastritis pain, gall bladder pain, and pancreatitis pain.
 12. A method for treating a subject suffering from an affliction associated with a particular cranial nerve, the method comprising administering to an ear canal of a subject an effective amount of a pharmaceutical composition comprising at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.
 13. The method of claim 12, wherein the composition further comprises at least one analgesic comprising a pyrazolone derivative.
 14. The method of claim 12, wherein the affliction comprises a neurology-psychiatry-related affliction, ear-nose-throat (ENT)-related affliction, Gastroenterology/Urology (GU)-related affliction, gastrointestinal (GI)-related affliction, cardiac-related affliction, pulmonary-related affliction, metabolic-related affliction, infection-related affliction, skin-related affliction, cell proliferation-related affliction, or blood flow-related affliction.
 15. The method of claim 14, wherein the neurology-psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-Traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Dysautonomia, Familial Intentional Tremor, Migraine pain, Autism Spectrum Disorder, Anxiety Headache, sleeplessness, Reticular Activating System (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent Pain, opiate withdrawal, Dysarthria, ADHD, Nonspecific hand tremor, Stuttering, cerebral palsy, Raynaud's Phenomenon, excessive sweating, reflex sympathetic dystrophy, sensory processing disorder, and decreased libido.
 16. The method of claim 14, wherein the ear-nose-throat (ENT)-related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, neck pain, Dry Eye Syndrome, Trigeminal Neuralgia pain, and Temporomandibular Joint Pain.
 17. The method of claim 14, wherein the Gastroenterology/Urology (GU)-related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis, Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain, enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation, frequent urination, Prolonged Vaginal Bleeding, decreased renal blood flow, chronic renal failure.
 18. The method of claim 14, wherein the gastrointestinal (GI)-related affliction is at least one selected from the group consisting of: irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic, Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronic constipation, Chronic diarrhea, and Pancreatitis.
 19. The method of claim 14, wherein the cardiac-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation, Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiac surgery derived cough, heart block, Atrial Contractions, Tachycardia, Congestive Heart Failure, premature atrial contraction, and atrial tachycardia.
 20. The method of claim 14, wherein the pulmonary-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and Bronchospasm.
 21. The method of claim 14, wherein the metabolic-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, hypercholesteremia, and insulin resistance.
 22. The method of claim 14, wherein the infection-related affliction is at least one selected from the group consisting of: Herpes Simplex 1 infection, Herpes, Simplex 2 infection, and Varicella Zoster infection.
 23. The method of claim 14, wherein the skin-related affliction is at least one selected from the group consisting of: facial flushing, facial blushing, alopecia areata, atopic dermatitis, chronic eczema, acne vulgaris, oily skin, rosacea, and morgellons disease.
 24. The method of claim 14, wherein the cell proliferation-related affliction is at least one selected from the group consisting of: cancer and mastocytosis.
 25. The method of claim 14, wherein the blood flow-related affliction is at least one selected from the group consisting of erectile dysfunction, open wound healing, and sickle cell disease. 